Chelator compositions comprising α-diamine compounds

ABSTRACT

The present invention involves photoprotective compositions which are useful for topical application to prevent damage to skin caused by acute or chronic exposure to ultraviolet light comprising chelating agents having the structure: ##STR1## wherein each --R 1  is independently selected from the group consisting of alkyl, aryl, heteroaryl and heterocycle, or the --R 1  &#39;s are covalently bonded together to form a cyclic alkyl or heterocyclic ring; --R 2  and --R 3  are --OR 4 , in which case there is no bond or a polar bond between --R 2  and the nitrogen covalently bonded to --R 3 , each --R 4  being independently selected from the group consisting of hydrogen, alkyl and aryl, except that both --R 4  &#39;s are not methyl when both --R 1  &#39;s are furyl; or --R 2  is --O-- and is covalently bonded to the nitrogen which is covalently bonded to --R 3 , and --R 3  is --O-- (there being a + charge on the nitrogen to which it is bonded) or nil; 
     wherein the α-diamine compounds consist essentially of compounds wherein ═NR 2  and ═NR 3  are in amphi configuration when both --R 2  and --R 3  are --OH, and when both --R 1  &#39;s are furyl or the --R 1  &#39;s are covalently bonded together to form a cyclohexanedione structure. 
     Methods for using such compositions to prevent damage to skin caused by acute or chronic exposure to ultraviolet light are also involved.

This is a continuation-in-part of application Ser. No. 514,892, filed onApr. 25, 1990, now abandoned.

TECHNICAL FIELD

This invention relates to pharmaceutical compositions useful forregulating biochemical and cellular damage resulting from free radicalreactions in living persons.

This invention further relates to topical compositions useful forprotecting the skin from the harmful effects of ultraviolet irradiation,such as sunburn and sun-induced premature aging of the skin.

BACKGROUND OF THE INVENTION

The damaging effects of sunlight on skin are well documented. Muchdamage is due to routine day-to-day activities in the sunlight.

The major short term hazard of prolonged exposure to sunlight iserythema (i.e., sunburn). The 290 to 320 nanometer wavelengthultraviolet radiation range, designated as the "UVB" wavelength range,tends to be the primary cause of erythema. The 320 to 400 nanometerwavelength ultraviolet radiation range, designated as the "UVA"wavelength range, also produces erythema.

In addition to the short term hazard of erythema, there are also longterm hazards associated with UV radiation exposure. One of these longterm hazards is malignant changes in the skin surface. Numerousepidemiologic studies demonstrate a strong relationship between sunlightexposure and human skin cancer. Another long term hazard of ultravioletradiation is premature aging of the skin. This condition ischaracterized by wrinkling and yellowing of the skin, along with otherphysical changes such as cracking, telangiectasis (spider vessels),solar keratoses (growths), ecchymoses (subcutaneous hemorrhagiclesions), and loss of elasticity (sagging). The adverse effectsassociated with exposure to UVA and UVB wavelength radiation are morefully discussed in DeSimone, "Sunscreen and Suntan Products", Handbookof Nonprescription Drugs, 7th Ed, Chapter 26, pp. 499-511 (AmericanPharmaceutical Association, Washington, D.C.; 1982); Grove and Forbes,"A Method for Evaluating the Photoprotection Action of Sunscreen AgentsAgainst UV-A Radiation", International Journal of Cosmetic Science, 4,pp. 15-24 (1982); and U.S. Pat. No. 4,387,089, DePolo, issued Jun. 7,1983. Hence, although the immediate effects of ultraviolet radiation maybe cosmetically and socially gratifying, the long-term hazards arecumulative and potentially serious.

Sunblock agents are commercially available to protect the skin from UVradiation. These agents scatter or reflect ultraviolet radiation.Examples include titanium dioxide and zinc oxide. However, these agentsare very susceptible to rub-off or wear-off resulting in little or noprotection.

The most common agents for sun protection are sunscreens. These agentsexert their effects through absorption of ultraviolet radiation so thatit cannot penetrate the skin. Sunscreens must remain on the surface ofthe skin during exposure. However, sunscreens are easily rubbed off orwashed off by sweating or swimming and can also be lost by penetrationinto the skin.

Conjugated dienoic acids and their derivatives, in general, are known tobe useful as quenchers for protecting the skin from harmful effects ofUV exposure. For example, the use of a number of compounds, including2,4-hexadien-1-ol, for controlling the chronic effects of prolongedexposure to sunlight is disclosed in U.S. Pat. No. 4,098,881, Majeti,issued Jul. 4, 1978. The use of sorbic acid or salts thereof insunscreen formulations is also known. See e.g., U.S. Pat. No. 4,264,581,Kerkhof et al., issued Apr. 28, 1981.

Tocopherol (Vitamin E) and its esters have been disclosed for use as aphotoprotector in topical compositions, without interfering with thetanning response. See, e.g., U.S. Pat. No. 4,144,325, Voyt, issued Mar.13, 1974; U.S. Pat. No. 4,248,861, Schutt, issued Feb. 3, 1981; U.S.Pat. No. 4,000,276, Hasunuma et al., issued Dec. 28, 1976; U.S. Pat. No.4,847,071, Bissett, Bush, and Chatterjee, issued Jul. 11, 1989; andEuropean Patent Application 166,221, Tuominen, published Jan. 2, 1986.

Hart, Cosmetics and Toiletries, 93(12), 28-30 (1978), discloses theutilization of low levels of chelating agents such asethylenediaminetetraacetic acid (EDTA) in cosmetic formulations aspreservatives. Particularly disclosed is the use of EDTA in sunscreenlotions and creams to prevent dark color formation from the reaction ofp-aminobenzoic acid derivatives with iron. See also, Hart, Cosmetics andToiletries, 98(4), 54-58 (1983). Japanese Patent Application 61-215,314discloses a topical composition for protecting skin from UV-rayscontaining EDTA or a phosphoric acid or salt,4-(1,1-dimethylethyl)-4'-methoxydibenzoylmethane and inorganic powders.The acids and their salts are added as preservatives. See also JapanesePatent Application 61-215,313, published Sep. 25, 1986, and U.S. Pat.No. 4,579,844, Rovee, issued Apr. 1, 1986. Wooley, et al., Biochem. J.,169, 265-276 (1978), discloses the inhibition of skin collagenaseutilizing EDTA, 1,10-phenanthroline, cysteine, dithiothreitol, or sodiumaurothiemaleate.

It is well-known that ultraviolet light induces inflammation of the skinand harmful photochemical reactions therein. During exposure and asrepair of the UV damage takes place, super-oxide (O₂ ⁻) radicals areformed in the skin. UV irradiation also causes some microvascular damagein the skin. (See Kligman et al., Photoderm., 3, 215-227 (1986)). Thisleads to local hemorrhage and "leakage" of blood cells into the dermis.Iron from the hemoglobin accumulates in the extra-cellular matrix of thetissue as Fe⁺² and Fe⁺³. It is known that iron catalyticallyparticipates in the conversion of superoxide radicals to hydroxylradicals, a species which is known to be very damaging to tissue. (SeeDavies, J. Biol. Chem., Vol. 262, No 20 (1987), pp. 9895-9901.) Anotherprocess which is damaging to tissue is membrane lipid peroxidation,which is also accelerated by iron. (See Halliwell and Gutteridge, FreeRadicals in Biology and Medicine, Claredon Press, Oxford, England(1985), p. 147.)

In addition to their role in UV radiation induced tissue damage, oxygenradicals are known to be capable of reversibly or irreversibly damagingcompounds of all biochemical classes, including nucleic acids, proteinsand free amino acids, lipids and lipoproteins, carbohydrates, andconnective tissue macromolecules. These compounds may have an impact onsuch cell activities as membrane function, metabolism, and geneexpression. (See C. E. Cross, G. Halliwell, E. T. Borish, W. A. Pryor,B. N. Ames, R. L. Saul, J. M. McCord, and D. Harman, "Oxygen Radicalsand Human Disease", Annals of Internal Medicine 107(4), 526-545 (1987).)Clinical conditions in which oxygen radicals are thought to be involvedinclude those concerning multiorgan involvement, includinginflammatory-immune injury such as glomerulonephritis (idiopathic,membranous), vasculitis (hepatitis B virus, drugs), autoimmune disease;ischemia-reflow states; drug and toxin-induced reactions; iron overloadsuch as idiopathic hemochromatosis, dietary iron overload (red wine,beer brewed in iron pots), thalassemia and other chronic anemias;nutritional deficiencies, such as Kwashiorkor, vitamin E deficiency;alcohol; radiation injury; aging, such as disorders of "prematureaging", immune deficiency of age; cancer and amyloid diseases.Additional conditions in which oxygen radicals are thought to beinvolved include those concerning primary single organ involvementincluding erythrocyte related conditions, such as phenylhydrazine,primaquine, lead poisoning, protoporphyrin photo-oxidation, malaria,sickle-cell anemia, favism, Fanconi anemia; lung related conditions suchas cigarette-smoking effects, emphysema, hyperoxia, bronchopulmonarydysplasia, oxidant pollutants, acute respiratory distress syndrome,mineral dust pneumoconiosis, bleomycin toxicity, paraquat toxicity;heart and cardiovascular system related conditions, such as alcoholcardiomyopathy, Keshan disease (selenium deficiency), atherosclerosis,doxorubicin toxicity; kidney related conditions, such as nephroticantiglomerular basement membrane disease, aminoglycoside nephrotoxicity,heavy metal nephrotoxicity, renal graft rejection; gastrointestinaltract related conditions, such as endotoxin liver injury, carbontetrachloride liver injury, diabetogenic action of alloxan,free-fatty-acid-induced pancreatitis,nonsteroidal-anti-inflammatory-drug induced lesions; jointabnormalities, such as rheumatoid arthritis; brain related conditions,such as hyperbaric oxygen, neurotoxins, senile dementia, Parkinsondisease-MPTP, hypertensive cerebrovascular injury, cerebral trauma,neuronal ceroid lipofuscinoses, allergic encephalomyelitis and otherdemyelinating diseases, ataxia-telangiectasia syndrome, potentiation oftraumatic injury, aluminum overload, a-beta-lipoproteinemia; eye relatedconditions, such as cataractogenesis, ocular hemorrhage, degenerativeretinal damage, retinopathy of prematurity, photic retinopathy and skinrelated conditions, such as solar radiation, thermal injury, porphyria,contact dermatitis, photosensitive dyes, and bloom syndrome. (See Cross,et. al., 1987.)

Black, Photochem. Photobiol., 46(2), 213-221 (1987), speculates, basedon circumstantial evidence, that free radicals may cause at least someUV-induced skin damage. The effect of systemically or intraperitoneallyadministered anti-oxidants on peroxide formation is discussed.

Braughler, et al., J. Biol. Chem., 261(22), 10282-10289 (1986),discusses iron-initiated lipid peroxidation reactions in the context ofbrain synoptosomes. It is shown that the use of a chelator, EDTA, willprevent the reactions from starting.

Nunez et al., J. Biol. Chem., 258(2), 1146-1151 (1983), discusses thecellular mechanism by which iron is released by reticulocytes. It wasfound that iron (II) chelators (e.g., phenanthroline, dipyridyl), butnot iron (III) chelators, were useful in the study of this mechanism.

deMello Filho, et al., Biochem. et Biophys. Acta, 847, 82-89 (1985),describes cell culture work which suggests that the inhibition of theiron-initiated peroxidation reaction by phenanthroline may preventcellular damage caused by inflammation.

Morgan, Biochem. Biophys. Acta, 733(1), 39-50 (1983), discusses themechanism by which certain iron chelators inhibit cellular iron uptakeafter release from transfertin while it is still in the membranefraction of the cells.

European Patent Application 0 313 305, Bissett, Bush, and Chatterjee,published Apr. 26, 1989, discloses photoprotection compositionscomprising various chelating agents, including 2-furildioxime.

It is an object of the present invention to provide a pharmaceuticalcomposition, the use of which will regulate biochemical damage resultingfrom free radical reactions in living persons.

It is also an object of the present invention to provide a method forregulating biochemical damage resulting from free radical reactions inliving persons.

It is also an object of the present invention to provide a topicalcomposition in a stable form, the use of which will prevent chronic(photoaging) effects of exposure to the sun.

It is also an object of the present invention to provide a topicalcomposition for preventing the deleterious effects of the sun withminimal interference to the tanning response.

It is also an object of the present invention to provide a cleansingcomposition for preventing the deleterious effects of the sun withminimal interference to the tanning response.

It is also an object of the present invention to provide a method forpreventing the deleterious effects of the sun with minimal interferenceto the tanning response.

It is further an object of the present invention to provide aphotoprotection composition which penetrates into the skin and which haslow susceptiblility to rub-off, wear-off or wash-off.

It is a still further object of the present invention to provide aphotoprotection composition which can be applied to the skin in advanceof UV exposure without significant loss of efficacy.

SUMMARY OF THE INVENTION

The present invention relates to a pharmaceutical composition comprisinga safe and effective amount of one or more α-diamine compounds havingthe structure: ##STR2## wherein each --R¹ is independently selected fromthe group consisting of alkyl, aryl, heteroaryl and heterocyclic, or the--R¹ 's are covalently bonded together to form a cyclic alkyl orheterocyclic ring; --R² and --R³ are --OR⁴, in which case there is nobond or a polar bond between --R² and the nitrogen covalently bonded to--R³, each --R⁴ being independently selected from the group consistingof hydrogen, alkyl and aryl, except that both --R⁴ 's are not methylwhen both --R¹ 's are furyl; or --R² is --O-- and is covalently bondedto the nitrogen which is covalently bonded to --R³, and --R³ is --O--there being a + charge on the nitrogen to which it is bonded) or nil;wherein the α-diamine compounds consist essentially of compounds wherein═NR² and ═NR³ are in amphi configuration when both --R² and --R³ are--OH, and when both --R¹ 's are furyl or the --R¹ 's are covalentlybonded together to form a cyclohexanedione structure.

The present invention also relates to a composition useful for topicalapplication comprising a safe and photoprotectively effective amount ofa chelating agent having structure (I) in combination with a topicalcarrier.

The present invention further relates to methods of regulating thedeleterious effects of free radical reactions in living tissue includingthe deleterious effects of ultraviolet exposure to the skin.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, "amphi", "amphi form", and "amphi position" refer to thepositioning of the --R² and --R³ groups of the present inventionrelative to one another such that the --R² and --R³ groups point in thesame direction as opposed to anti or syn forms wherein the --R² and --R³groups point in opposite directions away from or toward each other,respectively.

As used herein, "alkyl" means carbon-containing chains which may bestraight, branched, or cyclic; substituted or unsubstituted; and whichmay be saturated, monounsaturated (i.e., one double or triple bond inthe chain), or polyunsaturated (i.e., two or more double bonds in thechain; two or more triple bonds in the chain; one or more double and oneor more triple bonds in the chain). Unless otherwise indicated, alkylare preferably as follows. Preferred alkyl are straight or branchedchain, more preferably straight chain. Preferred alkyl areunsubstituted. Preferred alkyl are saturated or monounsaturated, morepreferably saturated. As used herein, "alkanyl" means a saturated alkylgroup. Preferred alkyl are C₁ -C₂₀, more preferably C₁ -C₁₈, morepreferably still C₁ -C₁₂, more preferably C₁ -C₆, more preferably C₁-C₂, most preferably C₁.

As used herein, "aryl" and "heteroaryl" mean aryl or heteroaryl ringswhich may be substituted or unsubstituted, preferably mono-, di-, ortri-substituted or unsubstituted, more preferably mono-substituted orunsubstituted, most preferably unsubstituted. Preferred heteroaryl ringscomprise at least one oxygen, nitrogen, or sulfur atom in the ringstructure. Preferred aryls are phenyl, naphthyl and hydroxyphenyl,especially phenyl. Preferred heteroaryls include furyl, thienyl,pyrrolyl, imidazolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl,isoquinolyl, purinyl, phthalazinyl, quinoxalinyl, furazanyl, isoxazolyl,and tetrazolyl; more preferred are furyl, thienyl and pyrrolyl,especially furyl.

As used herein, "heterocyclic" means cyclic rings having at least onering atom that is other than carbon, preferably nitrogen, oxygen orsulfur. Heterocyclic rings may be unsaturated, but are not aromatic.Preferred heterocyclic rings are saturated. Heterocyclic rings may besubstituted or unsubstituted, preferably unsubstituted. Preferredheterocyclic rings are saturated analogs of the above-specifiedheteroaryl rings, especially tetrahydrofuryl.

As used herein, "substituted", in reference to alkyl, aryl, heteroarylor heterocyclic groups, means such groups that can be mono- orpolysubstituted. Preferred is mono-, di- or trisubstituted; morepreferred is monosubstituted. Preferred substituents are selected fromthe group consisting of halogen, hydroxy, amino, nitro, thiol, aryl,alkyl and --OR wherein --R is aryl or alkyl.

As used herein, "biochemical damage" means damage (resulting in apossible impact on such cell activities as membrane function,metabolism, and gene expression) to compounds of any biochemical class,including, but not limited to, nucleic acids, proteins and free aminoacids, lipids and lipoproteins, carbohydrates, and connective tissuemacromolecules.

As used herein, "cellular damage" means damage to cell activitiesincluding, but not limited to, membrane function, metabolism, and geneexpression.

As used herein, "chelation" means the removal of a metal ion from asystem by forming a complex so that the metal ion cannot readilyparticipate in or catalyze chemical reactions.

As used herein, "safe and effective amount" means an amount of compoundor composition sufficient to significantly induce a positivemodification in the condition to be treated, but low enough to avoidserious side effects (at a reasonable benefit/risk ratio), within thescope of sound medical judgment. The safe and effective amount of thecompound or composition will vary with the particular condition beingtreated, the age and physical condition of the patient being treated,the severity of the condition, the duration of the treatment, the natureof concurrent therapy, the specific compound or composition employed,the particular pharmaceutically-acceptable carrier utilized, and likefactors within the knowledge and expertise of the attending physician.

As used herein when referring to composition ingredients, "compatible"means that the particular ingredient in question is capable of beingcommingled with the chelating agent and other ingredients in a mannersuch that there is no interaction which would substantially reduce theefficacy of the composition of the present invention.

As used herein, "free radical" means an atom or group of atoms with anunpaired electron.

As used herein, "free radical reaction" means the reaction of a freeradical with another substance.

As used herein, "parenteral administration" means introduction of acomposition by injection, such as intraperitoneal, intravenous,subcutaneous, intramuscular, or intramedullary.

As used herein, "regulating" means preventing, retarding, or arresting.

As used herein, "safe and photoprotectively effective amount" means anamount of agent or composition sufficient to substantially reduce thedeleterious effects of UV-radiation to skin but not so much as to causeserious side effects or adverse skin reactions.

As used herein, all percentages are by weight unless otherwisespecified.

Although the present invention is not limited to any particularmechanism, it is believed that the present invention works wholly orpartly by operation of the following mechanism. Certain metal chelatorsare able to "tie-up" free iron or facilitate its removal from a targettissue, thus impairing its catalytic activity, thus protecting the skinfrom aging effects caused by UV exposure. By "tying up" free iron, thesolubility of the iron is changed and therefore may be removed from thattissue and subsequently excreted or removed to a tissue where damage isless likely. In addition, by impairing the catalytic activity of metalions in the human body, the compositions of the present inventionprevent, arrest, or retard diseases and disorders in living beings inwhich free radicals, particularly oxygen radicals, have been implicatedas a pathogen. For example, various insults to a person's body (e.g.,injury, disease, or U.V. irradiation) lead to small amounts of freeradical formation. These small amounts of free radicals may be amplifiedcatalytically by transition metals in the body, such as iron. Theresulting free radicals may be more reactive, toxic and deleterious tobiological tissue. In addition, the increased concentration of freeradicals may also result in more deleterious effects to biologicaltissue. For further examples of free radical reactions, see Cross, C.E., G. Halliwell, E. T. Borish, W. A. Pryor, B. N. Ames, R. L. Saul, J.M. McCord, and D. Harmon, "Oxygen Radicals and Human Disease", 107Annals of Internal Medicine 526 (1987).

Chelating agents useful in compositions and methods of the presentinvention have the following structural formula: ##STR3## wherein each--R¹ is independently selected from the group consisting of alkyl, aryl,heteroaryl and heterocyclic, or the --R¹ 's are covalently bondedtogether to form a cyclic alkyl or heterocyclic ring; --R² and --R³ are--OR⁴, in which case there is no bond or a polar bond between --R² andthe nitrogen covalently bonded to --R³, each --R⁴ being independentlyselected from the group consisting of hydrogen, alkyl and aryl exceptthat both --R⁴ 's are not methyl when both --R¹ 's are furyl; or --R² is--O-- and is covalently bonded to the nitrogen which is covalentlybonded to --R³, and --R³ is --O-- (there being a + charge on thenitrogen to which it is bonded) or nil; wherein the compounds consistessentially of compound wherein ═NR² and ═NR³ are in amphi configurationwhen both --R² and --R³ are --OH, and when both --R¹ 's are furyl or the--R¹ 's are covalently bonded together to form a cyclohexanedionestructure.

Preferably both --R¹ 's are the same moiety. Preferably both --R⁴ 's arethe same moiety.

When --R¹ is aryl, --R¹ is preferably selected from substituted andunsubstituted, preferably unsubstituted, 2-hydroxyphenyl and phenyl.

When --R¹ is heteroaryl, --R¹ is preferably selected from substitutedand unsubstituted, preferably unsubstituted, 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 2-pyrrolyl, 2-imadazolyl, 1-pyrazolyl,2-pyrazinyl, 2-pyrimidinyl, 3-pyridazinyl, 3-isoquinolyl, 8-purinyl,1-phthalazinyl, 2-quinoxalinyl, 3-furazanyl, 3-isoxazolyl, 2-tetrazolyland 5-tetrazolyl; more preferably from 2-furyl, 3-furyl, 2-thienyl,3-thienyl and 2-pyrrolyl; more preferably still from 2-furyl and3-furyl. Most preferably --R¹ is 2-furyl.

When --R¹ is heterocyclic, --R¹ is preferably the saturated analog ofthe preferred heteroaryls specified in the previous paragraph; mostpreferred is 2-tetrahydrofuryl.

When --R¹ is alkyl, --R¹ is preferably selected from substituted andunsubstituted, preferably unsubstituted, C₁ -C₂₀ alkyl, more preferablyC₁ -C₁₈, more preferably C₁ -C₁₂, more preferably still C₁ -C₆, morepreferably C₁ -C₂, most preferably C₁. Preferred alkyl --R¹ 's arealkanyls. Preferred alkanyls are straight chain.

When --R¹ is substituted, each substituent is preferably selected fromalkyl and aryl. When the substituent is an alkyl, it is preferablyselected from C₁ -C₂₀ alkyl, more preferably C₁ -C₁₈, more preferably C₁-C₁₂, more preferably still C₁ -C₆, more preferably C₁ -C₂, mostpreferably C₁. When the substituent is an aryl, it is preferably phenyl.

Preferred chelating agents useful in the present invention include thosehaving the following structural formula: ##STR4## wherein --R¹ is asdefined hereinabove.

Preferred chelating agents useful in the present invention include thosehaving the following structural formula: ##STR5## wherein --R¹ and --R⁴are as defined hereinabove. Preferably such compounds are in the amphiconfiguration.

Most preferably --R⁴ is hydrogen.

When --R⁴ is aryl, it is unsubstituted or substituted, preferablyunsubstituted; preferably --R⁴ is phenyl. When --R⁴ is a substitutedaryl, the substituent is preferably --OH.

When --R⁴ is alkyl, it is unsubstituted or substituted, preferablyunsubstituted, preferably selected from C₁ -C₂₀, more preferably C₂-C₁₈, more preferably C₂ -C₁₂, more preferably C₂ -C₆, more preferablystill C₂ -C₄, most preferably C₂. When --R⁴ is a substituted alkyl,preferred substituents are selected from --OH, ═O, carboxy, --NH₂,--NHR⁷ and --NR⁷ ₂, wherein --R⁷ is alkyl or aryl.

Preferred compounds for use in the present invention include di-(2-furyl) ethanedione amphi-dioxime, di-(5-methyl-2-furyl) ethanedioneamphi-dioxime, di-(4-methyl-2-furyl) ethanedione amphi-dioxime,di-(5-ethyl-2-furyl) ethanedione amphi-dioxime, di-(4-ethyl-2-furyl)ethanedione amphi-dioxime, di-(5-propyl -2-furyl) ethanedioneamphi-dioxime, and di-(4-propyl-2-furyl) ethanedione amphi-dioxime; morepreferred are di-(2-furyl) ethane-dione amphi-dioxime,di-(5-methyl-2-furyl) ethanedione amphidioxime, di-(4-methyl-2-furyl)ethanedione amphi-dioxime, di-(5-ethyl-2-furyl) ethanedioneamphi-dioxime, and di-(4-ethyl-2-furyl) ethanedione amphi-dioxime; stillmore preferred is di-(2-furyl) ethanedione amphi-dioxime. Representativestructures include ##STR6##

Compounds also preferred for use in the present invention includedi-(2-thienyl) ethanedione amphi-dioxime, di-(5-methyl-2-thienyl)ethanedione amphi-dioxime, di-(4-methyl-2-thienyl) ethanedioneamphi-dioxime, di-(5-ethyl-2-thienyl) ethanedione amphi-dioxime, anddi-(5-propyl-2-thienyl) ethanedione amphidtoxime; more preferred aredi-(2-thienyl) ethanedione amphi-dioxime, di-(5-methyl-2-thienyl)ethanedione amphi-dioxime, and di-(4-methyl-2-thienyl) ethanedioneamphi-dioxime; still more preferred is di-(2-thienyl) ethanedioneamphi-dioxime. Representative structures include: ##STR7##

Compounds also preferred for use in the present invention includedi-(2-pyrrolyl) ethanedione amphi-dioxime, di-(5-methyl-2-pyrrolyl)ethanedione amphi-dioxime, di-(4-methyl-2-pyrrolyl) ethanedioneamphi-dioxime, di-(5-ethyl-2-pyrrolyl) ethanedione amphi-dioxime,di-(4-ethyl-2-pyrrolyl) ethanedione amphi-dioxime,di-(5-propyl-2-pyrrolyl) ethanedione amphi-dioxime, anddi-(5-propyl-2-pyrrolyl) ethanedione amphi-dioxime; more preferred aredi-(2-pyrrolyl) ethanedione amphi-dioxime, di-(5-methyl-2-pyrrolyl)ethanedione amphi-dioxime, di-(4-methyl-2-pyrrolyl) ethanedioneamphi-dioxime, di-(5-ethyl-2-pyrrolyl) ethanedione amphi-dioxime, anddi-(4-ethyl-2-pyrrolyl) ethanedione amphidioxime; still more preferredare di-(2-pyrrolyl) ethanedione amphi-dioxime, di-(5-methyl-2-pyrrolyl)ethanedione amphi-dioxime, and di-(4-methyl-2-pyrrolyl) ethanedioneamphi-dioxime; more preferred still is di-(2-pyrrolyl) ethanedioneamphi-dioxime. Representative structures include ##STR8##

Compounds also preferred for use in the present invention includedi-(1-methyl-2-pyrrolyl) ethanedione amphi-dioxime,di-(1,5-dimethyl-2-pyrrolyl) ethanedione amphi-dioxime,di-(1-methyl-5-ethyl-2-pyrrolyl) ethanedione amphi-dioxime,di-(1-methyl-5-propyl-2-pyrrolyl) ethanedione amphi-dioxime, anddi(1-methyl-2-pyrrolyl) ethanedione amphi-dioxime; more preferred aredi-(1-methyl-2-pyrrolyl) ethanedione amphi-dioxime,di-(1,5-dimethyl-2-pyrrolyl) ethanedione amphi-dioxime,di-(1-methyl-dimethyl-2-pyrrolyl) ethanedione amphi-dioxime,di-(1-methyl-5-propyl-2-pyrrolyl) ethanedione amphi-dioxime; still morepreferred is di-(1-methyl-2-pyrrolyl) ethanedione amphi-dioxime.Representative structures include: ##STR9##

Compounds also preferred for use in the present invention include:##STR10##

Compounds also preferred for use in the present invention includedi-(4-ethylphenyl) ethanedione amphi-dioxime, di-(3-ethylphenyl)ethanedione amphi-dioxime, di-(4-propylphenyl) ethanedioneamphi-dioxime, di-(2-hydroxy) ethanedione amphi-dioxime, anddi-(2-hydroxy-4-ethylphenyl) ethanedione amphi-dioxime; more preferredare di-(4-ethylphenyl) ethanedione amphi-dioxime, di-(3-ethylphenyl)ethanedione amphi-dioxime, di-(4-propylphenyl) ethanedioneamphi-dioxime; still more preferred is di-(4-ethylphenyl) ethanedioneamphi-dioxime. Representative structures include: ##STR11##

Compounds also preferred for use in the present invention include4,5-di-(2-furyl) furoxan and 4,5-di-(2-thienyl) furoxan; preferably4,5-di-(2-furyl) furoxan, a representative structure of which is asfollows: ##STR12##

Also preferred for incorporation in the compositions of the presentinvention are mixtures of any of the above compounds.

A compound also preferred for use in the present invention isamphi-1,2-cyclohexanedione, which is represented by the followingstructure ##STR13##

Also preferred for incorporation in the compositions of the presentinvention are mixtures of the above amphi-form compounds, except fordi-(2-furyl) ethanedione amphi-dioxime and amphi-1,2-cyclohexanedione,with their corresponding anti- and syn-forms. Typically such mixturesare about half amphi-form and about half anti-form with very little(less than about 2%) syn-form. For compounds named herein, lack ofdesignation of a particular form is non-specific and denotes either theamphi-form alone or a mixture of it with the other forms; any suchmixture is preferably at least 40% amphi-form, more preferably at least60% amphi-form, more preferably still at least 80% amphi-form.

Another aspect of the present invention relates to novel compoundshaving the structural formula ##STR14## wherein --R⁴ is as defined ashereinbefore; --B is independently selected from the group consisting ofalkyl, aryl, or heteroaryl; preferably alkyl; more preferably C₂ -C₂₀alkyl; more preferably a C₂ -C₆ alkyl; more preferably ethyl. --B ispreferably bonded to the 4-position.

Another aspect of the present invention relates to novel compoundshaving the structural formula ##STR15## wherein --R⁴ and --B are asdefined hereinbefore; --B is preferably bonded to the 5-position,

Another aspect of the present invention relates to novel compoundshaving the structural formula: ##STR16## wherein --R⁴ and --B are asdefined hereinbefore; --B is preferably bonded to the 5-position.

Test Method I Standard Method for Assay of Ornithine Decarboxylase

Scope: This method describes an assay procedure for the determination ofthe enzyme ornithine decarboxylase (ODC) in mouse skin epidermis. Theassay is linear up to at least 40 minutes of incubation of enzyme withsubstrate, with a deviation between replicates of less than 10%. Themethod is based on published procedures for determination of mouseepidermal ODC. (See Lowe, N., A. K. Verma, and R. K. Boutwell, Journalof Investigational Dermatology, Vol. 71 (1978), pp. 417-418; Verma, A.K., N. J. Lowe & R. K. Boutwell, Cancer Research, Vol. 39 (1979), pp.1035-1040; Binder, R. L., N. E. Volpenheim & A. A. Motz, Carcinogenesis,Vol. 10 (1989), pp. 2351-2357; and Hillebrand, G. G., N. S. Winslow, M.J. Benzinger, D. A. Heitmeyer & D. L. Bissett, "Acute and ChronicUltraviolet Radiation Induction of Epidermal Ornithine DecarboxylaseActivity in Hairless Mice", Cancer Research, Vol. 50 (1990) pp.1580-1584.

Principle: A homogenate of mouse epidermal tissue is incubated withcarbon 14-labeled L-ornithine, the substrate for the enzyme. The enzymecatalyzes the release from ornithine of ¹⁴ CO₂, which is trapped withbenzethonium hydroxide. The ¹⁴ C is then counted versus substrate todetermine amount of liberated CO₂. The amount of liberated CO₂ is usedto determine the level of enzyme present in the tissue. There are noavailable standards for this mouse skin enzyme. Previous work (seeHillebrand) has indicated the conditions under which this assay can bedone to obtain a linear correspondence between time of enzyme-substrateincubation and release of ¹⁴ CO₂.

Chemicals:

1. NaH₂ PO₄ ·H₂ O

2. Na₂ HPO₄ ·7H₂ O

3. EDTA (ethylene diamine tetracetic acid), disodium, dihydrate

4. PLP (pyridoxal phosphate)

5. DTT (dithiothreitol)

6. L-ornithine.HCl

7. L-[1-¹⁴ C]-ornithine·HCl (52 mCi/mmole; Dupont NEN Products, Boston,Mass.)

8. Anhydrous citric acid

9. Methylbenzethonium hydroxide (1M solution in methanol; Sigma ChemicalCo., St. Louis, Mo.)

10. Bio-Rad Protein Assay Kit--based on Bradford protein assay (SeeRandford, M., Anal. Biochemistry, Vol. 72 (1976), p. 248.)

See note at end of method.

Equipment:

1. Clear polystyrene tubes (12×75 mm, #14-956-3D, Fisher Scientific,Pittsburgh, Pa.)

2. Tissue homogenizer - Tissuemizer (type SDT-1810, Tekmar, Co.,Cincinnati, Ohio)

3. 1.5 ml polypropylene micro test tubes (#223-9500, Bio-RadLaboratories, Richmond, Calif.)

4. Eppendorf centrifuge (model 5415; Brinkman Instruments Inc.,Westbury, N.Y.)

5. Pasteur pipettes.

6. Cryogenic vials (#07753-0308), Vangard Cryos, Vangard InternationalInc., Neptune, N.J.)

7. 15×85 mm and 16×150 mm glass test tubes

8. 37° C. shaking water (Aquatherm water bath shaker model R-86, NewBrunswick Scientific Co., New Brunswick, N.J.)

9. Kontes Scientific (Vineland, N.J.) rubber stoppers (#882310-0000) andcenter well assemblies (#882320-0000)

10. Magnetic stirrer and Teflon-coated magnetic stir bars

11. Glass beakers (100, 250 and 500 ml sizes, and 1 and 2 liter sizes)

12. 50 ml polypropylene centrifuge tubes (#25331, Corning Glass Works,Corning, N.Y.)

13. Vortex mixer

14. Spectrophotometer (model 260, Gilford Instrument Laboratories, Inc.,Oberlin, Ohio)

15. Whatman No. 1 filter paper

16. Polypropylene funnel

See note at end of method.

Preparation of Special Reagents:

1. Homogenization buffer: Homogenization buffer=50 mM sodium phosphate,1.25 mM EDTA, 2.5 mM DTT and 0.1 mM PLP [pH 7.1].

(a) Dissolve 3.45 g of NaH₂ PO₄ ·7H₂ O and 0.23 g EDTA in 400 ml ofdistilled-deionized water; bring volume to 500 ml:

50 mM monobasic sodium phosphate+1.25 mM EDTA.

(b) Dissolve 6.7 g of Na₂ HPO₄.·H₂ O and 0.23 g of EDTA in 400 ml ofdistilled-deionized water; bring volume to 500 ml:

50 mM dibasic sodium phosphate+1.25 mM EDTA.

Combine 250 ml of (a) with 500 ml of (b) to yield 750 ml of pH 7.1phosphate-EDTA buffer. Add 0.289 g of DTT to 750 ml of phosphate-EDTAbuffer and then 0.0185 g of PLP to 750 ml of phosphate-EDTA-DTT bufferto prepare final homogenization buffer. This is prepared in advance andkept frozen at -20° C. in 50-ml aliquats in 50 ml polypropylenecentrifuge tubes until needed. Then it is thawed, and kept on ice.

2. Substrate solution: Substrate solution=1.6 mM L-ornithine, 0.65 mMPLP, 20 micro Ci/ml L-[¹⁴ C]-ornithine.

Dissolve 34 mg of L-ornithine in 100 ml of water. To this is added 20 mgof PLP. This is frozen in 1-ml aliquats until used. Mix 1 ml of theornithine-PLP mixture with 0.25 ml (25 micro Ci) of L-[1-¹⁴ C]-ornithinehydrochloride (52 mCi/mmole; Dupont NEN Products, Boston, Mass.). Thissubstrate solution is de-gassed (to remove any ¹⁴ CO₂) by pulling apartial vacuum (aspirator) on the solution three times, each of 30seconds duration. This solution is then kept at room temperature untilused.

3. Citric acid solution: Dissolve 384 g of citric acid in 600 ml ofwater; bring the volume up to 1000 ml: 2M citric acid (pH 1.5). This isprepared in advance and kept frozen at -20° C. in 50-ml aliquats in 50ml polypropylene centrifuge tubes until needed. Then it is thawed, andkept at room temperature.

4. Dye Reagent: Dilute 1 volume of Dye Reagent Concentrate with 4volumes of distilled-deionized water. Filter through Whatman No. 1filter paper and store dilute reagent in a glass container at roomtemperature. Prepare just before use.

5. Protein standard: The Bio-Rad Protein Standard supplied in the kit islyophilized bovine protein sealed under nitrogen. To reconstitute, add20 ml of distilled-deionized water which will yield a proteinconcentration of 1.4 mg/ml. This protein solution is stored at -20° C.until needed. Then it is thawed, and kept at room temperature.

Mouse Treatment and Irradiation. A chelator to be screened is dissolvedin a liquid vehicle; preferred vehicles are ethanol, isopropanol, water,propylene glycol, or mixtures thereof. The test material solution is 5%(w/v) chelator (or saturated with chelator if the chelator is notsoluble at 5% in any reasonable vehicle).

Test material solutions are applied topically to the dorsal skin of themouse. A control group of mice receives topical application of the samevehicle as is in the test material solution (without the chelatingagent). Test material solution or control vehicle is applied to the skinof each mouse at an application rate of approximately 2 μl/cm². Topicaltreatments are done three times: AM and PM of Day 1 and AM of Day 2.

Two hours after the third treatment, the dorsal skin of the mice isexposed to 2X MED (minimum erythemal dose}with a 1000-watt Xenon arcsolar simulator. The total UV dose is approximately 1.6 J/cm².Twenty-four hours after irradiation, mice are sacrificed by cervicaldislocation, and the dorsal skin is removed.

Procedure:

1. Whole dorsal skin from a mouse is placed dermis side down on an icecold glass plate. The epidermal side of the skin is scraped with a razorblade 20 times to remove the epidermis, which adheres to the razorblade.

2. Epidermal shave scrapings are transferred to individual 12×75 mmclear polystyrene tubes containing 0.6 ml of ice cold homogenizationbuffer.

3. Using a Tissuemizer homogenizer, the tissue is homogenized on ice for20 seconds at a homogenizer power control setting of 80 (0-100 scale).

4. The homogenate is transferred to a 1.5 ml polypropylene micro testtube and centrifuged at 16,000×g for 10 minutes at 4° C. in an Eppendorfcentrifuge.

5. The clear supernatant solution is transferred with a Pasteur pipetteto a 1.2 cc cryogenic vial.

6. Add 0.1 ml of supernatant solution to a 15×85 mm glass test tube andplace in a 37° C. shaking water bath for 5 minutes. Duplicate assays arerun for each sample. Six blank assays containing 0.1 ml ofhomogenization buffer are also run.

7. The assay is started by addition of 0.025 ml of de-gassed substratesolution. This gives a final concentration of assay components of 40 mMsodium phosphate, 1 mM EDTA, 2 mM DTT, 0.2 mM PLP, 0.4 mM ornithine, and0.5 micro Ci of ¹⁴ C-ornithine. The assay tube is immediately sealedwith a rubber stopper and center well assembly, the center wellcontaining 0.1 ml of methylbenzethonium hydroxide. The reaction is runat 37° C. in a shaker water bath at 50 rpm for 30 minutes.

8. Using a disposable 1 ml plastic syringe fitted with a 22 gauge1.5-inch needle, the assay is stopped by piercing the rubber stopper andinjecting 0.25 ml of 2M citric acid solution into the assay solution.Particular care is taken not to inject citric acid into the center wellassembly.

9. The assay mixture is kept at room temperature for 30 minutes aftercitric acid injection to ensure complete absorption of ¹⁴ CO₂ bymethylbenzethonium hydroxide contained in the center well.

10. The center well bucket is transferred, by cutting with scissors thecenter well stem, to scintillation vials containing 10 ml ofscintillation fluid and shaken thoroughly. Standards are prepared byadding 0.025 ml of substrate solution to 10 ml of scintillation fluid;this amount of ¹⁴ C represents total conversion of substrate to CO₂ inthe assay.

11. Content of ¹⁴ C is determined with a scintillation counter.

12. Determine protein content of homogenate by the Bio-Rad ProteinAssay. Place 0.02 ml of homogenate and 0.08 ml of water in a test tube(16×150 mm). As blanks, 0.02 ml of homogenization buffer is used. Allassays are done in duplicate. Add 5 ml of diluted dye reagent. Mix on avortex mixer. After 5 minutes to 1 hour, measure OD₅₉₅ versus blanks.Protein content of samples is read from a plot of OD₅₉₅ versusconcentration of protein standards (20-140 microgram).

Calculations: Based on the total dpm in the L-[¹⁴ C]-ornithine standard,the dpm per pmole of ¹⁴ C can be derived. The following equations arethen used to calculate ODC activity on the basis of protein: ##EQU1##The Ornithine Decarboxylase (ODC) value (pmole/hr mg) for the chelatorbeing screened is compared to the ODC value (pmole/hr mg) for thecontrol to give a percent difference between the two values. Preferredcompounds useful in the present invention demonstrate at least a 20%decrease in the ODC value as compared to the ODC value of the control.

NOTE: The chemicals and equipment specified in these sections aredescribed in detail as to properties, dimensions, and suggestedsuppliers for the convenience of those doing the assay. Unless otherwiseindicated, alternate sources of equivalent chemicals and equipment maybe used, providing that they meet the requirements necessary to preservethe accuracy and precision of the assay method.

Test Method II In Vivo Mouse Skin Wrinkling Test

A second test useful for screening chelators for photoprotectivecapability is the in vivo mouse skin wrinkling test which measurespremature wrinkling inhibition, described in D. L. Bissett, D. P. Hannon& T. V. Orr, "An Animal Model of Solar-Aged Skin: Histological,Physical, and Visible Changes in UV-Irradiated Hairless Mouse Skin",Photochem. Photobiol., Vol. 46 (1987), pp. 367-378; and D. L. Bissett,G. G. Hillebrand and D. P. Hannon, "The Hairless Mouse as a Model ofSkin Photoaging: Its Use to Evaluate Photoprotective Materials",Photodermatology, Vol. 6 (1989), pp. 228-233.

The test is used to determine the photoprotective efficacy of topicallyapplied materials against UVB-induced photo-aging. The work is done withSkh:HR-1 hairless mice.

A chelator to be screened is dissolved in a liquid vehicle; preferredvehicles are ethanol, isopropanol, water, propylene glycol, or mixturesthereof. The test material solution is 5% (w/v) chelator (or saturatedwith chelator if the chelator is not soluble at 5% in any reasonablevehicle).

Test material solutions are applied topically to the dorsal skin of themouse. A control group of mice receives topical application of the samevehicle as is in the test material solution (without the chelatingagent). Test material solution or control vehicle is applied to the skinof each mouse at an application rate of approximately 2/μl/cm². Topicaltreatments are done three times each week.

A bank of four 4-foot fluorescent UVB lamps (Westinghouse FS-40sunlamps) is used. The energy output of the lamps is measured with anInternational Light (Newburyport, Mass.) model 700 A researchradiometer. Mice are irradiated with 30 mJ/cm² of UVB per exposure.Irradiations are done two hours after each topical application of thetest material solution or vehicle.

Once each week, mice are observed for skin wrinkling and tumor formation(see Bissett, et al., Photochem. Photobiol., Vol. 46 (1987), pp. 367-378and Bissett, et al., Photodermatology, Vol. 6 (1989), pp. 228-233.Wrinkles are graded on a 0-3 scale, and tumors are counted as describedin these references. The test is continued until the skin wrinkle gradeof the control group is at least about 2.0 and the tumors are recountedat this point; generally the test requires about 20 weeks to complete.

Chelating agents which exhibit at least about a 20% reduction in skinwrinkle grade in Test Method II are useful in the present invention.Preferred chelating agents exhibit at least about a 30% reduction inskin wrinkle grade; more preferred chelating agents exhibit at leastabout a 60% reduction in skin wrinkle grade; most preferred chelatingagents exhibit at least about a 90% reduction in skin wrinkle grade.

A composition of the present invention may be tested using Test MethodII to determine its effective dosage levels and appropriate formulationsand methods of application. For example, if a chelator shown to beeffective using Test Method I is shown in Test Method II to be arelatively ineffective photoprotective agent due to its inability topenetrate the skin, it may be formulated with a skin penetrationenhancer to enhance its efficacy.

A safe and effective amount of a chelating agent is used in thecompositions of the present invention. Typically, this is from about0.1% to about 10%, preferably from about 0.5% to about 5% of thecomposition.

It is important to note that, when used for purposes of photoprotection,the chelating agent is predominantly a non-sunscreen photoprotectingagent. A sunscreen works on the surface of the skin to absorb UVradiation so that the harmful rays never enter the skin. The chelatingagent works in the skin to prevent damaging reactions in the skin.Because the chelating agent penetrates the skin to work, rub-off,wear-off or wash-off of the active, which lessen efficacy for sunscreensconsiderably, are essentially irrelevant with the present invention.Furthermore, though critical with a sunscreen, it is not necessary tokeep an even coating of the active of the present invention on the skinfor the entire exposure period. The chelating agent can be applied tothe skin up to four hours or longer prior to UV exposure. The chelatingagent protects against both acute effects of UV exposure, e.g., sunburn,and chronic effects of UV exposure, e.g., premature aging of the skin.

Carriers

In addition to the chelating agent as described hereinbefore, thepharmaceutical compositions of the present invention essentiallycomprise a pharmaceutically-acceptable carrier. The term"pharmaceutically-acceptable carrier", as used herein, means one or morecompatible solid or liquid filler diluents or encapsulating substanceswhich are suitable for administration to a human or lower animal.Pharmaceutically-acceptable carriers must, of course, be of sufficientlyhigh purity and sufficiently low toxicity to render them suitable foradministration to the human or lower animal being treated. A safe andeffective amount of carrier is from about 80% to about 99%, preferablyfrom about 90% to about 98%, of the composition.

Variations in formulation of these carriers will result in a widevariety of products which fall within the scope of the presentinvention.

A. Topical Carriers

The topical pharmaceutical/cosmetic compositions of the presentinvention may be made into a wide variety of product types. Theseinclude, for example, lotions, creams, beach oils, gels, sticks, sprays,ointments, pastes, mousses and cosmetics. These product types maycomprise either of two basic types of carrier systems, solutions andemulsions.

The topical pharmaceutical/cosmetic compositions of the presentinvention formulated as solutions typically include a pharmaceutically-or cosmetically-acceptable aqueous or organic solvent. The terms"pharmaceutically-acceptable aqueous solvent", "cosmetically-acceptableaqueous solvent", "pharmaceutically-acceptable organic solvent" and"cosmetically-acceptable organic solvent" refer to a solvent which, inaddition to being capable of having dispersed or dissolved therein thechelating agent, also possesses acceptable safety (e.g., irritation andsensitization characteristics), as well as good aesthetic properties(e.g., does not feel greasy or tacky). Water is a typical aqueoussolvent. Examples of suitable organic solvents include: propyleneglycol, polyethylene glycol (200-600), polypropylene glycol (425-2025),glycerol, 1,2,4-butanetriol, sorbitol esters, 1,2,6-hexanetriol,ethanol, isopropanol, butanediol, and mixtures thereof. These solutionscontain from about 0.01% to about 20%, more preferably from about 0.5%to about 10%, more preferably from about 1% to about 5% of the chelatingagent, and from about 80% to about 99.99%, more preferably from about90% to about 99.5%, more preferably from about 95% to about 99% of anacceptable organic solvent.

If the topical pharmaceutical/cosmetic compositions of the presentinvention are formulated as an aerosol and applied to the skin as aspray-on, a propellant is added to a solution composition. Examples ofpropellants useful herein include, but are not limited to, thechlorinated, fluorinated and chloro-fluorinated lower molecular weighthydrocarbons. A more complete disclosure of propellants useful hereincan be found in Sagaran, Cosmetics Science and Technology, 2nd Edition,Vol. 2, pp. 443-465 (1972).

Topical pharmaceutical/cosmetic compositions of the present inventionmay be formulated as a solution comprising an emollient. An example of acomposition formulated in this way would be a beach oil product. Suchcompositions contain from about 0.1% to about 20% of the chelating agentand from about 1% to about 50% of a topicalpharmaceutically/cosmetically-acceptable emollient.

As used herein, "emollients" refer to materials used for the preventionor relief of dryness, as well as for the protection of the skin. A widevariety of suitable emollients are known and may be used herein.Sagaran, Cosmetics, Science and Technology, 2nd Edition, Vol. 1, pp.32-43 (1972), incorporated herein by reference, contains numerousexamples of suitable materials.

A lotion can be made from a solution carrier system. Lotions typicallycomprise from about 0.1% to about 20%, preferably from about 0.5% toabout 10%, of the chelating agent; from about 1% to about 20%,preferably from about 5% to about 10%, of an emollient; and from about50% to about 90%, preferably from about 60% to about 80%, water. Anothertype of product that may be formulated from a solution carrier system isa cream. A cream of the present invention would comprise from about 0.1%to about 20%, preferably from about 0.5% to about 10%, of the chelatingagent; from about 5% to about 50%, preferably from about 10% to about20%, of an emollient, and from about 45% to about 85%, preferably fromabout 50% to about 75%, water.

Yet another type of product that may be formulated from a solutioncarrier system is an ointment. An ointment may comprise a simple base ofanimal or vegetable oils or semi-solid hydrocarbons (oleaginous).Ointments may also comprise absorption ointment bases which absorb waterto form emulsions. Ointment carriers may also be water soluble. Anointment may also comprise from about 2% to about 10% of an emollientplus from about 0.1% to about 2% of a thickening agent. A more completedisclosure of thickening agents useful herein can be found in Segarin,Cosmetics, Science and Technology, 2nd Edition, Vol. 1, pp. 72-73(1972).

If the carrier is formulated as an emulsion, from about 1% to about 10%,preferably from about 2% to about 5%, of the carrier system comprises anemulsifier. Emulsifiers may be nonionic, anionic or cationic. Suitableemulsifiers are disclosed in, for example, U.S. Pat. No. 3,755,560,issued Aug. 28, 1973, Dickert et al,; U.S. Pat. No. 4,421,769, issuedDec. 20, 1983, Dixon et al.; and McCutcheon's Detergents andEmulsifiers, North American Edition, pages 317-324 (1986); thedisclosures of which are incorporated herein by reference. Preferredemulsifiers are anionic or nonionic, although the other types may alsobe used.

Single emulsion skin care preparations, such as lotions and creams, ofthe oil-in-water type and water-in-oil type are well-known in thecosmetic art and are useful in the present invention. Multiphaseemulsion compositions, such as the water-in-oil-in-water type, asdisclosed in U.S. Pat. No. 4,254,105, Fakuda et al., issued Mar. 3,1981, herein incorporated by reference, are also useful in the presentinvention. In general, such single or multiphase emulsions containwater, emollients and emulsifiers as essential ingredients.

Triple emulsion carrier systems comprising an oil-in-water-in-siliconefluid emulsion composition as disclosed in U.S. Pat. No. 4,960,764,herein incorporated by reference, are also useful in the presentinvention. This triple emulsion carrier system can be combined with fromabout 0.1% to about 20%, preferably from about 0.5% to about 10%, of thechelating agent to yield the topical pharmaceutical/cosmetic compositionof the present invention.

Another emulsion carrier system useful in the topicalpharmaceutical/cosmetic compositions of the present invention is amicro-emulsion carrier system. Such a system comprises from about 9% toabout 15% squalane; from about 25% to about 40% silicone oil; from about8%, to about 20% of a fatty alcohol; from about 15% to about 30% ofpolyoxyethylene sorbitan mono-fatty acid (commercially available underthe trade name Tweens) or other nonionics; and from about 7% to about20% water. This carrier system is combined with from about 0.5% to about10% of the chelating agent.

Lotions and creams can be formulated as emulsions as well as solutions.Typically such lotions comprise from about 0.1% to about 20%, preferablyfrom about 0.5% to about 10%, of the chelating agent; from about 1% toabout 20%, preferably from about 5% to about 10%, of an emollient; fromabout 25% to about. 75%, preferably from about 45% to about 95%, water;and from about 0.1% to about 10%, preferably from about 0.5% to about5%, of an emulsifier. Such creams would typically comprise from about0.1% to about 20%, preferably from about 0.5% to about 10%, of thechelating agent; from about 1% to about 20%, preferably from about 5% toabout 10%, of an emollient; from about 20% to about 80%, preferably fromabout 30% to about 70%, water; and from about 1% to about 10%,preferably from about 2% to about 5%, of an emulsifier.

If the topical pharmaceutical/cosmetic compositions of the presentinvention are formulated as a gel or a cosmetic stick, a suitable amountof a thickening agent, as disclosed supra, is added to a cream or lotionformulation.

The topical pharmaceutical/cosmetic compositions of the presentinvention may also be formulated as makeup products such as foundations,or lipsticks.

The topical pharmaceutical/cosmetic compositions of the presentinvention may contain, in addition to the aforementioned components, awide variety of additional oil-soluble materials and/or water-solublematerials conventionally used in topical compositions, at theirart-established levels.

Various water-soluble materials may also be present in the compositionsof this invention. These include humectants, proteins and polypeptides,preservatives and an alkaline agent. In addition, the topicalcompositions herein can contain conventional cosmetic adjuvants, such asdyes, opacifiers (e.g., titanium dioxide), pigments and perfumes.

The topical pharmaceutical/cosmetic compositions of the presentinvention may also include a safe and effective amount of a penetrationenhancing agent. A safe and effective amount is generally from about 1%to about 5% of the composition. Examples of useful penetrationenhancers, among others, are disclosed in U.S. Pat. Nos. 4,537,776,Cooper, issued Aug. 27, 1985; 4,552,872, Cooper et al., issued Nov. 12,1985; 4,557,934, Cooper, issued Dec. 10, 1985; 4,130,667, Smith, issuedDec. 19, 1978; 3,989,816, Rhaadhyaksha, issued Nov. 2, 1976; 4,017,641,DiGiulio, issued Apr. 12, 1977; and European Patent Application 0043738,Cooper et al., published January 13, 1982.

Other conventional skin care product additives may also be included inthe compositions of the present invention. For example, collagen,hyaluronic acid, elastin, hydrolysates, primrose oil, jojoba oil,epidermal growth factor, soybean saponins, mucopolysaccharides, andmixtures thereof may be used.

Various vitamins may also be included in the compositions of the presentinvention. For example, Vitamin A, and derivatives thereof, Vitamin B₂,biotin, pantothenic, Vitamin D, and mixtures thereof may be used.

A. Oral Dose Forms

Various oral dosage forms can be used, including such solid forms astablets, capsules, granules, bulk powders and microcapsules of the drug.These oral forms comprise a safe and effective amount, usually at leastabout 5%, and preferably from about 25% to about 50% of the compound ofthe present invention. Tablets can be compressed, enteric-coated,sugar-coated or film-coated containing suitable binders, lubricants,surfactants, diluents, disintegrating agents, coloring agents, flavoringagents, preservatives, flow-inducing agents, and melting agents. Liquidoral dosage forms include aqueous and nonaqueous solutions, emulsions,suspensions, solutions and/or suspensions reconstituted fromnon-effervescent granules, containing suitable solvents, preservatives,emulsifying agents, suspending agents, diluents, sweeteners, meltingagents, coloring agents, and flavoring agents. Preferred carriers fororal administration include gelatin and propylene glycol. Specificexamples of pharmaceutically-acceptable carriers and excipients that maybe used in formulating oral dosage forms containing compounds of thepresent invention are described in U.S. Pat. No. 3,903,297, Robert,issued Sep. 2, 1975, incorporated by reference herein. Techniques andcompositions for making solid oral dosage forms are described inMarshall, "Solid Oral Dosage Forms," Modern Pharmaceutics, Vol. 7,(Banker and Rhodes, editors), 359-427 (1979). Techniques andcompositions for making tablets (compressed, formulas and molded),capsules (hard and soft gelatin) and pills are described in Remington'sPharmaceutical Sciences (Arthur Osol, editor), 1553-1593 (1980).

The preferred unit dosage forms for oral administration are tablets,capsules and the like, comprising a safe and effective amount of acompound of the present invention. Preferably oral dose forms comprisefrom about 1000 mg to about 0.1 mg of a chelating agent of the presentinvention, more preferably from about 500 mg to about 1 mg, and mostpreferably from about 100 mg to about 5 mg.

C. Injectable Dose Forms

The compounds of the present invention are also useful when injected.The dosage of the compound of the present invention which is both safeand effective to provide free radical reaction regulating activity willvary with the particular condition being treated, the severity of thecondition, the duration of treatment, the specific compound employed andits usage concentration, and like factors within the specific knowledgeand expertise of the attending physician and commensurate with areasonable benefit/risk ratio associated with the use of any drugcompound. The injectable dosages and dosage ranges given herein arebased on delivery of the compound of the present invention to a 70 kghuman and can be adjusted to provide equivalent dosages for patients ofdifferent body weights.

Methods and materials for manufacturing injectables can be found inRemington's Pharmaceutical Sciences, 17ed., 1985, Chapter 85, p. 1518.Materials for use in injectables are also described more fullyhereinafter.

Generally, three types of injectable dosage forms are preferred: 1)aqueous solutions; 2) non-aqueous solutions; and 3) emulsions. The abovedosage forms typically contain from about 0.001 mg/ml to about 10 mg/mlof a compound of the present invention, preferably from about 0.1 mg/mlto about 1 mg/ml, more preferably from about 0.4 mg/ml to about 0.6mg/ml.

Injectable dose forms for regulating free radical reactions in the humanbody typically comprise from about 1000 mg to about 0.1 mg, andpreferably from about 100 mg to about 1 mg, of the chelating agent ofthe present invention.

Cleaning Compositions

The skin cleaning compositions of the present invention comprise, inaddition to the chelating agent, a cosmetically-acceptable surfactant.The term "cosmetically-acceptable surfactant" refers to a surfactantwhich is not only an effective skin cleanser, but also can be usedwithout undue toxicity, irritation, allergic response, and the like.Furthermore, the surfactant must be capable of being commingled with thechelating agent in a manner such that there is no interaction whichwould substantially reduce the efficacy of the composition forprotecting the skin from the effects of UV radiation.

The skin cleaning compositions of the present invention contain fromabout 0.1% to about 25%, preferably from about 0.5% to about 10%, of thechelating agent and from about 1% to about 90%, preferably from about50% to about 85%, of a cosmetically acceptable surfactant.

The physical form of the skin cleansing compositions is not critical.The compositions can be, for example, formulated as toilet bars,liquids, pastes, or mousses. Toilet bars are most preferred since thisis the form of cleansing agent most commonly used to wash the skin.

The surfactant component of the compositions of the present inventionare selected from anionic, nonionic, zwitterionic, amphoteric andampholytic surfactants, as well as mixtures of these surfactants. Suchsurfactants are well-known to those skilled in the detergency art.

The cleaning compositions of the present invention can optionallycontain, at their art-established levels, materials which areconventionally used in skin cleansing compositions.

Combination Actives

A Sunscreens and Sunblocks

Optimum protection against sun damage can be obtained by using acombination of the non-sunscreening photoprotection agent of the presentinvention together with sunscreens or sunblocks. Useful sunblocksinclude, for example, zinc oxide and titanium dioxide.

The photoprotecting capability of the chelating agent is primarilyagainst UVB radiation. Thus, the combination of the chelating agent witha UVA sunscreen would be most desirable. Additional UVB protection mayalso be included in such compositions. The inclusion of sunscreens incompositions of the present invention at low levels will notsignificantly reduce the tanning response of the user but will enhanceimmediate protection against acute UV damage.

A wide variety of conventional sunscreening agents are suitable for usein combination with the chelating agent. Segarin, et al., at ChapterVIII, pages 189 et seq., of Cosmetics Science and Technology, disclosenumerous suitable agents. Specific suitable sunscreening agents include,for example: p-Aminobenzoic acid, its salts and its derivatives (ethyl,isobutyl, glyceryl esters; p-dimethylaminobenzoic acid); Anthranilates(i.e., o-aminobenzoates; methyl, menthyl, phenyl, benzyl, phenylethyl,linalyl, terpinyl, and cyclohexenyl esters); Salicylates (amyl, phenyl,benzyl, menthyl, glyceryl, and dipropyleneglycol esters); Cinnamic acidderivatives (menthyl and benzyl esters, α-phenyl cinnamonitrile; butylcinnamoyl pyruvate); Dihydroxycinnamic acid derivatives (umbelliferone,methylumbelliferone, methylaceto-umbelliferone); Trihydroxycinnamic acidderivatives (esculetin, methylesculetin, daphnetin, and the glucosides,esculin and daphnin); Hydrocarbons (diphenylbutadiene, stilbene);Dibenzalacetone and benzalacetophenone; Naphtholsulfonates (sodium saltsof 2-naphthol-3,6-disulfonic and of 2-naphthol-6,8-disulfonic acids);Dihydroxy-naphthoic acid and its salts; o- andp-Hydroxybiphenyldisulfonates; Coumarin derivatives (7-hydroxy,7-methyl, 3-phenyl); Diazoles (2-acetyl-3-bromoindazole, phenylbenzoxazole, methyl naphthoxazole, various aryl benzothiazoles); Quininesalts (bisulfate, sulfate, chloride, oleate, and tannate); Quinolinederivatives (8-hydroxyquinoline salts, 2-phenylquinoline); Hydroxy- ormethoxy-substituted benzophenones; Uric and vilouric acids; Tannic acidand its derivatives (e.g., hexaethylether); (Butyl carbotol) (6-propylpiperonyl) ether; Hydroquinone; Benzophenones (Oxybenzene,Sulisobenzone, Dioxybenzone, Benzoresorcinol, 2,2',4,4'-Tetrahydroxybenzophenone, 2,2'-Dihydroxy-4,4'-dimethoxybenzophenone,Octabenzone; 4-Isopropyldibenzoylmethane; Butylmethoxydibenzoylmethane;Etocrylene; and 4-isopropyl-di-benzoylmethane.

Of these, 2-ethylhexyl p-methoxycinnamate, 4,4'-t-butylmethoxydibenzoylmethane, 2-hydroxy-4-methoxybenzophenone, octyldimethylp-aminobenzoic acid, digalloyltrioleate,2,2-dihydroxy-4-methoxybenzophenone, ethyl4-[bis(hydroxypropyl)]aminobenzoate2-ethylhexyl-2-cyano-3,3-diphenylacrylate, 2-ethylhexylsalicylate,glyceryl p-aminobenzoate, 3,3,5-trimethylcyclohexylsalicylate,methylanthranilate, p-dimethyl-aminobenzoic acid or aminobenzoate,2-ethylhexyl p-dimethylamino-benzoate, 2-phenylbenzimidazole-5-sulfonicacid, 2-(p-dimethylaminophenyl)-5-sulfonicbenzoxazoic acid and mixturesof these compounds, are particularly useful.

Preferred sunscreens useful in the compositions of the present inventionare 2-ethylhexyl p-methoxycinnamate, butylmethoxydibenzoylmethane,2-hydroxy-4-methoxybenzophenone, octyldimethyl p-aminobenzoic acid andmixtures thereof.

A safe and photoprotectively effective amount of sunscreen may be usedin the chelating agent compositions of the present invention. Thesunscreening agent must be compatible with the chelating agent.Generally the composition may comprise from about 1% to about 20%,preferably from about 2% to about 10%, of a sunscreening agent. Exactamounts will vary depending upon the sunscreen chosen and the desiredSun Protection Factor (SPF). Because of the chelating agent'sphotoprotecting capability against erythema, the combination provides anSPF greater than that of the sunscreen alone.

Also particularly useful in the present invention are sunscreens such asthose disclosed in Sabatelli, U.S. Pat. No. 4,937,370 and Sabatelli etal., U.S. Pat. No. 4,834,983. The sunscreening agents disclosed thereinhave, in a single molecule, two distinct chromophore moieties whichexhibit different ultra-violet radiation absorption spectra. One of thechromophore moieties absorbs predominantly in the UVB radiation rangeand the other absorbs strongly in the UVA radiation range.

Preferred members of this class of sunscreening agents are4-N,N-(2-ethylhexyl)methylaminobenzoic acid ester of2,4-dihydroxybenzophenone; N,N-di-(2-ethylhexyl)-4-aminobenzoic acidester with 4-hydroxydibenzoylmethane; 4-N,N-(2-ethylhexyl)methylaminobenzoic acid ester with 4-hydroxydibenzoylmethane;4-N,N-(2-ethylhexyl)methylaminobenzoic acid ester of2-hydroxy-4-(2-hydroxyethoxy)benzophenone; 4-N,N-(2-ethylhexyl)methylaminobenzoic acid ester of 4-(2-hydroxyethoxy)dibenzoylmethane;N-N-di-(2-ethylhexyl)-4-aminobenzoic acid ester of2-hydroxy-4-(2-hydroxyethoxy)benzophenone; andN,N-di-(2-ethylhexyl)-4-aminobenzoic acid ester of4-(2-hydroxyethoxy)dibenzoylmethane and mixtures thereof.

The compositions of the present invention, with or without sunscreens,may also be formulated as shampoos, conditioners, mousses or other haircare products. It is known that UV radiation damages hair and thephotoprotecting agents of the present invention may minimize suchdamage. Furthermore such formulations will provide a means for applyingthe photoprotecting agents of the present invention onto the scalp,which is also susceptible to UV damage. Any compatible art-recognizedhair care formulations can be used with the chelating agent added at alevel of from about 1% to about 5%. If desired, a sunscreen may also beincluded at from about 1% to about 5%.

An agent may also be added to any of the compositions of the presentinvention to improve the skin substantivity of those compositions,particularly to enhance their resistance to being washed off by water,or rubbed off. A preferred agent which will provide this benefit is acopolymer of ethylene and acrylic acid. Compositions comprising thiscopolymer are disclosed in U.S. Pat. No. 4,663,157, Brock, issued May 5,1987, which is incorporated herein by reference.

B. Anti-Inflammatory Agents

In a preferred photoprotection composition of the present invention, ananti-inflammatory agent is included as an active along with thechelating agent. The inclusion of an anti-inflammatory agent enhancesthe photoprotection benefits of the compositions. The anti-inflammatoryagent protects strongly in the UVA radiation range (though it alsoprovides some UVB protection as well), while the chelating agentprotects strongly in the UVB radiation range. Thus the combinationprovides broad protection. The topical use of anti-inflammatory agentsreduces photo-aging of the skin resulting from chronic exposure to UVradiation. (See U.S. Pat. No. 4,847,071, Bissett, Bush, and Chatterjee,issued Jul. 11, 1989; and U.S. Pat. No. 4,847,069, Bissett andChatterjee, issued Jul. 11, 1989.) It has also been discovered that thecombination of an anti-inflammatory agent and the chelating agentprovides greater photoprotection than is provided by each active alone.

A safe and photoprotectively effective amount of an anti-inflammatoryagent may be added to the compositions of the present invention,generally from about 0.1% to about 10%, preferably from about 0.5% toabout 5%, of the composition. The exact amount of anti-inflammatoryagent to be used in the compositions will depend on the particularanti-inflammatory agent utilized since such agents vary widely inpotency.

Steroidal anti-inflammatory agents, including but not limited to,corticosteroids such as hydrocortisone, hydroxyltriamcinolone,alpha-methyl dexamethasone, dexamethasone-phosphate, beclomethasonedipropionate, clobetasol valerate, desonide, desoxymethasone,desoxycorticosterone acetate, dexamethasone, dichlorisone, diflorasonediacetate, diflucortolone valerate, fluadrenolone, flucloroloneacetonide, fludrocortisone, flumethasone pivalate, fluosinoloneacetonide, fluocinonide, flucortine butylester, fluocortolone,fluprednidene (fluprednylidene) acetate, flurandrenolone, halcinonide,hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone,triamcinolone acetonide, cortisone, cortodoxone, flucetonide,fludrocortisone, difluorosone diacetate, fluradrenolone acetonide,medrysone, amcinafel, amcinafide, betamethasone and the balance of itsesters, chloroprednisone, chlorprednisone acetate, clocortelone,clescinolone, dichlorisone, difluprednate, flucloronide, flunisolide,fluoromethalone, fluperolone, fluprednisolone, hydrocortisone valerate,hydrocortisone cyclopentylpropionate, hydrocortamate, meprednisone,paramethasone, prednisolone, prednisone, beclomethasone dipropionate,triamcinolone, and mixtures thereof may be used. The preferred steroidalanti-inflammatory for use in the present invention is hydrocortisone.

A second class of anti-inflammatory agents which is useful in thecompositions of the present invention includes the nonsteroidalanti-inflammatory agents. The variety of compounds encompassed by thisgroup are well-known to those skilled in the art. For detaileddisclosure of the chemical structure, synthesis, side effects, etc., ofnon-steroidal anti-inflammatory agents, reference may be had to standardtexts, including Anti-inflammatory and Anti-Rheumatic Drugs, K. D.Rainsford, Vol. I-III, CRC Press, Boca Raton, (1985), andAnti-inflammatory Agents, Chemistry and Pharmacology, 1, R. A. Scherrer,et al., Academic Press, New York (1974).

Specific non-steroidal anti-inflammatory agents useful in thecomposition of the present invention include, but are not limited to:

1) the oxicams, such as piroxicam, isoxicam, tenoxicam, sudoxicam, andCP-14,304;

2) the salicylates, such as aspirin, disalcid, benorylate, trilisate,safapryn, solprin, diflunisal, and fendosal;

3) the acetic acid derivatives, such as diclofenac, fenclofenac,indomethacin, sulindac, tolmetin, isoxepac, furofenac, tiopinac,zidometacin, acematacin, fentiazac, zomepiract, clidanac, oxepinac, andfelbinac;

4) the fenamates, such as mefenamic, meclofenamic, flufenamic, niflumic,and tolfenamic acids;

5) the propionic acid derivatives, such as ibuprofen, naproxen,benoxaprofen, flurbiprofen, ketoprofen, fenoprofen, fenbufen,indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen,tioxaprofen, suprofen, alminoprofen, and tiaprofenic; and

6) the pyrazoles, such as phenybutazone, oxyphenbutazone, feprazone,azapropazgne, and trimethazone.

Mixtures of these non-steroidal anti-inflammatory agents may also beemployed, as well as the pharmaceutically-acceptable salts and esters ofthese agents. For example, etofenamate, a flufenamic acid derivative, isparticularly useful for topical application. Of the nonsteroidalanti-inflammatory agents, ibuprofen, naproxen, flufenamic acid,mefenamic acid, meclofenamic acid, piroxicam and felbinac are preferred;ibuprofen, naproxen, and flufenamic acid are most preferred.

Another class of anti-inflammatory agents which are useful in thepresent invention are the anti-inflammatory agents disclosed in U.S.Pat. No. 4,708,966, Loomans et al., issued Nov. 24, 1987. This patentdiscloses a class of nonsteroidal anti-inflammatory compounds whichcomprise specifically substituted phenyl compounds, especiallysubstituted 2,6-di- tert-butyl phenol derivatives. For example,compounds selected from 4-(4'-pentyn-3'-one)-2,6-di-t-butylphenol;4-(5'-hexynoyl)2,6-di-t-butylphenol;4-((S)-(-)-3'-methyl-5'-hexynoyl)-2,6-di-t-butylphenol;4-((R)-(+)-3'-methyl-5'-hexynoyl)-2,6-di-t-butylphenol; and4-(3',3'-dimethoxypropionyl)-2,6-di-t-butylphenol are useful in thepresent invention.

Yet another class of anti-inflammatory agents which are useful in thepresent invention are those disclosed in U.S. Pat. No. 4,912,248,Mueller, issued Mar. 27, 1990. This patent discloses compounds anddiastereomeric mixtures of specific 2-naphthyl- containing estercompounds, especially naproxen ester and naproxol ester compounds,having two or more chiral centers. For example, compounds selected from(S)-naproxen-(S)-2-butyl ester, (S)-naproxen-(R)-2-butylester,(S)-naproxol-(R)-2-methyl butyrate, (S)-naproxol-(S)-2-methyl butyrate,diasteromeric mixtures of (S)-naproxen-(S)-2-butyl ester and(S)-naproxen-(R)-2-butyl ester, and diasteromeric mixtures of(S)-naproxol-(R)-2-methyl butyrate and (S)-naproxol-(S)-2-methylbutyrate are useful in the present invention.

Finally, so-called "natural" anti-inflammatory agents are useful in thepresent invention. For example, candelilla wax, alpha bisabolol, aloevera, Manjistha (extracted from plants in the genus Rubia, particularlyRubia Cordifolia), and Guggal (extracted from plants in the genusCommiphora, particularly Commiphora Mukul), may be used.

An even more preferred composition of the present invention comprises achelating agent, a sunscreen, and an anti-inflammatory agent togetherfor photoprotection in the amounts disclosed for each individuallyhereinabove.

The photoprotection compositions of the present invention may comprise,in addition to the chelating agent, a safe and photoprotectivelyeffective amount of a radical scavenging compound, generally from about1% to about 20%, preferably from about 2% tc about 10%, more preferablyfrom about 3% to about 5% of the composition. Examples of such radicalscavenging compounds an ascorbic acid (Vitamin C) and its salts,tocopherol (Vitamin E), other tocopherol esters, butylated hydroxybenzoic acids and their salts,6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (commerciallyavailable under the tradename Trolox®), gallic acid and its alkylesters, especially propyl gallate, uric acid and its salts and alkylesters, sorbic acid and its salts, the ascorbyl esters of fatty acids,amines (e.g., N,N-diethylhydroxylamine, aminoguanidine), sulfhydrylcompounds (e.g., glutathione), and dihydroxyfumaric acid and its salts.Each of these compounds has photoprotecting capabilities. The use of theradical scavenger tocopherol sorbate in the present invention incombination with the chelating agent is preferred.

C. Anti-Oxidants/Radical Scavengers

In a preferred photoprotection composition of the present invention, ananti-oxidant/radical scavenger is included as an active along with thechelating agent. The inclusion of an anti-oxidant/radical scavengerincreases the photoprotection benefits of the composition.

A safe and photoprotectively effective amount of an anti-oxidant/radicalscavenger may be added to the compositions of the present invention,generally from about 0.1% to about 10%, preferably from about 1% toabout 5%, of the composition.

Anti-oxidants/radical scavengers such as ascorbic acid (vitamin C) andits salts, tocopherol (vitamin E), tocopherol sorbate, other esters oftocopherol, butylated hydroxy benzoic acids and their salts,6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (commerciallyavailable under the tradename Trolox®), gallic acid and its alkylesters, especially propyl gallate, uric acid and its salts and alkylesters, sorbic acid and its salts, the ascorbyl esters of fatty acids,amines (e.g., N,N-diethylhydroxylamine, amino-guanidine), sulfhydrylcompounds (e.g., glutathione), and dihydroxy fumaric acid and its saltsmay be used.

In a preferred photoprotection composition of the present invention,compositions comprise one, any two, or all three of a sunscreeningagent, anti-inflammatory agent, and/or an antioxidant/radical scavengingagent included as actives along with the chelating agent. The inclusionof two or all three of these agents with the chelator increases thephotoprotection benefits of the composition.

Methods for Regulating Biochemical Damage Caused by Free RadicalReactions in a Living Person

The present invention further relates to a method for regulatingbiochemical or cellular damage resulting from free radical reactions ina living person. Such a method comprises administering, preferablytopically, orally, or parenterally a safe and free radical regulatingeffective amount of the specifically defined chelating agents disclosedhereinabove to be useful in the present invention. The amount ofchelating agent and frequency of application will vary widely dependingupon the level of free radical reactions occurring in the subject andthe level of regulation of these reactions desired.

Typically, a safe and free radical regulating effective amount in atopical composition is from about 0.001 mg to about 1.0 mg, preferablyfrom about 0.01 mg to about 0.5 mg, more preferably from about 0.05 mgto about 0.1 mg of the chelating agent per cm² of skin. Applicationpreferably ranges from about I to about 6 times daily, more preferablyfrom about 2 to about 4 times daily. For particularly effectivecompositions once per day application is preferred.

A safe and free radical regulating effective amount in an orally dosedcomposition is from about 0.1 mg to about 1000 mg, more preferably fromabout 1 mg to about 500 mg, of the chelating agent per dose. Dosingwould range from about I to about 6 times daily, more preferably fromabout 2 to about 4 times daily. For particularly effective compositionsonce per day dosing is preferred.

A safe and free radical regulating effective amount of a parenterallydosed composition is from about 0.1 mg to about 1000 mg, more preferablyfrom about 1 mg to about 500 mg, of th chelating agent per dose. Dosingwould range from about 1 to about 6 times daily, more preferably fromabout 2 to about 4 times daily. For particularly effective compositionsonce per day dosing is preferred.

Method For Preventing Deleterious Effects Caused by UV Exposure

The present invention further relates to a method for protecting theskin of humans and lower animals from the deleterious effects of UVradiation. Such protection by the chelating agent extends to damageresulting from acute UV exposure, e.g. erythema. It also moreparticularly extends to protection from damage resulting from chronic UVexposure, e.g. photoaging. Such a method comprises applying to the skinof the human or lower animal a safe and photoprotectively effectiveamount of the chelating agents disclosed hereinabove to be useful in thepresent invention. This may be accomplished by using a compositioncomprising the chelating agent as disclosed hereinabove. The activesinvolved in each of the following methods may be simply spread over theskin, or rubbed into the skin to enhance penetration of the chelatingagent. The actives are applied in conjunction with UV exposure, i.e.,prior to, during, or after UV exposure. More specifically, the activesmay be applied several hours, preferably up to 4 hours, prior to UVexposure, up to 30 minutes after UV exposure, or anytime in between. Forprotection against acute damage from UV-radiation, application of theactives just prior to exposure is preferred. For protection againstchronic damage from UV radiation, application is preferably 1 to 5 timesdaily, more preferably about 2 times daily, but for particularlyeffective compositions preferably once daily. Typically a safe andphotoprotectively effective amount is from about 0.001 mg to about 1.0mg, preferably from about 0.01 mg to about 0.5 rag, more preferably fromabout 0.05 mg to about 0.1 mg of the chelating agent per cm² skin.

A preferred method of the present invention for preventing deleteriouseffects caused by UV exposure involves applying both a safe andphotoprotectively effective amount of a chelating agent and a safe andphotoprotectively effective amount of one or more of a sunscreeningagent, an anti-inflammatory agent, and/or a radical scavenging compound(as defined hereinbefore) to the skin simultaneously. By "simultaneousapplication" or "simultaneously" is meant applying the agents to theskin at the same situs on the body at about the same time. Though thiscan be accomplished by applying the agents separately to the skin,preferably a composition comprising all the desired agents commingled isapplied to the skin. The amount of sunscreening agent applied isgenerally from about 0.01 mg to about 1.0 mg, preferably from about 0.05mg to about 0.5 mg, per cm² of skin. The amount of radical scavengingcompound applied is generally from about 0.01 mg to about 1.0 mg,preferably from about 0.05 mg to about 0.5 mg, per cm² skin. The amountof anti-inflammatory agent is generally from about 0.005 mg to about 0.5mg, preferably from about 0.01 mg to about 0.1 mg.

The following examples further describe and demonstrate the preferredembodiments within the scope of the present invention. The examples aregiven solely for the purpose of illustration, and are not to beconstrued as limitations of the present invention since many variationsthereof are possible without departing from its spirit and scope.

EXAMPLE 1

A moisturizing lotion is prepared by combining the following componentsutilizing conventional mixing techniques.

    ______________________________________                                                               Percent by Weight                                      Components             of Composition                                         ______________________________________                                        Water (purified)       70.94                                                  Carbomer viscosity control agents                                                                    0.23                                                   (commercially available in the Acritamer                                      series from R.I.T.A. Corp.)                                                   Alkyl Parabens         0.90                                                   Glycerin               3.50                                                   Potassium Hydroxide    0.09-0.15                                              Tetrasodium EDTA       0.10                                                   Cetyl Alcohol          1.25                                                   Stearic Acid           0.75                                                   Glyceryl Stearate      0.63                                                   Polyoxyethylene Stearyl Alcohol                                                                      1.75                                                   (commercially available in the Brij series                                    from ICI Americas, Inc.)                                                      Coco-Caprylate/caprate 2.00                                                   C.sub.12 -C.sub.15 Alcohol Benzoate (Finsolv TN -                                                    2.00                                                   commercially available from Finetex, Inc.)                                    Di-(2-Furyl) Ethanedione Amphi-Dioxime                                                               2.00                                                   Octyl Methoxycinnamate 7.50                                                   Benzophenone-3         1.00                                                   Octyl Dimethyl PABA    1.00                                                   Dimethicone            0.30                                                   Imidazolidinyl Urea    0.10                                                   Ethylene Acrylate Copolymer                                                                          3.80                                                   Tyrosine               0.10                                                   ______________________________________                                    

This lotion may be topically applied to inhibit damage caused by acuteor chronic UV exposure. Use of an amount of lotion sufficient to depositabout 0.5 mg/cm² of di-(2-furyl) ethanedione amphi-dioxime, and about0.5 mg/cm² of the sunscreening agents to the skin immediately prior toUV exposure is appropriate.

EXAMPLE II

A skin lotion is prepared by combining the following componentsutilizing conventional mixing techniques.

    ______________________________________                                                               Percent by Weight                                      Component              Of Composition                                         ______________________________________                                        4-N,N-(2-Ethylhexyl)methylamino-                                                                     10.00                                                  benzoic Acid Ester of 4-(2-Hydroxyethoxy)-                                    dibenzoylmethane                                                              Water (purified)       45.54                                                  Dimethyl Isosorbide    9.00                                                   Dioctyl Maleate        8.00                                                   C.sub.12 -C.sub.15 Alcohol Benzoate (Finsolv TN-                                                     8.00                                                   commercially available from Finetex, Inc.)                                    Glycerin               3.50                                                   Ethylene Acrylate Copolymer                                                                          3.80                                                   Di-(5-Methyl-2-Thienyl) Ethanedione                                                                  2.00                                                   Dioxime                                                                       Tocopherol Sorbate     2.00                                                   Cetyl Alcohol          1.75                                                   Polyoxyethylene Stearyl Alcohol                                                                      1.75                                                   (commercially available in the Brij series                                    from ICI Americas, Inc.)                                                      Stearic Acid           1.25                                                   Glyceryl Stearate      1.13                                                   Alkyl Parabens         0.90                                                   Titanium Dioxide       0.40                                                   Dimethicone            0.30                                                   Carbomer viscosity control agents                                                                    0.23                                                   (commercially available in the Acritamer                                      series from R.I.T.A. Corp.)                                                   Imidazolidinyl Urea    0.10                                                   Potassium Hydroxide    0.15                                                   Tyrosine               0.10                                                   Tetrasodium EDTA       0.10                                                   ______________________________________                                    

This lotion is useful for topical application to inhibit damage causedby acute or chronic UV exposure. Use of an amount of lotion sufficientto deposit about 0.5 mg/cm² of di-(5-methyl-2-thienyl) ethanedionedioxime, about 0.5 mg/cm² tocopherol sorbate, and about 0.5 mg/cm² ofthe sunscreening agents to the skin up to 4 hours prior to UV exposureis appropriate.

EXAMPLE III

A suntan cream is prepared by combining the following componentsutilizing conventional mixing techniques.

    ______________________________________                                                               Percent by Weight                                      Component              of Composition                                         ______________________________________                                        Mineral Oil            20.00                                                  Octyl Palmitate        10.00                                                  Glyceryl Isostearate   4.00                                                   Octyl Methoxycinnamate 7.50                                                   Oxybenzone             3.00                                                   Polyethylene (AC-617-A,AC-6-A available                                                              2.00                                                   from Allied Chemical)                                                         Alkyl parabens         0.30                                                   Glycerin               2.00                                                   4,5-Di-(2-Thienyl) Furoxan                                                                           2.00                                                   Ibuprofen              1.00                                                   Water (purified)       q.s.                                                   ______________________________________                                    

This cream is useful for topical application to inhibit damage caused byacute or chronic UV exposure. Use of an amount of cream sufficient todeposit about 0.5 mg/cm² of 4,5-di-(2-thienyl) furoxan, about 0.5 mg/cm²of the sunscreening agents, and about 0.1 mg/cm² of ibuprofen to theskin immediately following UV-exposure is appropriate.

EXAMPLE IV

A suntan stick is prepared by combining the following componentsutilizing conventional mixing techniques.

    ______________________________________                                                               Percent by Weight                                      Component              of Composition                                         ______________________________________                                        Candelilla Wax         18.25                                                  Ozokerite Wax          18.25                                                  Petrolatum             18.25                                                  Lanolin                15.00                                                  Mineral Oil            14.85                                                  Octyl Dimethyl PABA    7.00                                                   Benzophenone-3         3.00                                                   BHA (preservative: butylated hydroxy                                                                 0.05                                                   anisole)                                                                      Propylparaben          0.10                                                   Di-(4-Ethyl-2-Furyl) Ethanedione Dioxime                                                             5.00                                                   Flavor                 q.s.                                                   ______________________________________                                    

This stick is useful for topical application, for example to the lips,to inhibit damage caused by acute or chronic UV exposure. Use of anamount of stick sufficient to deposit about 1.0 mg/cm² ofdi-(4-ethyl-2-furyl) ethanedione dioxime, and about 0.5 mg/cm² of thesunscreening agents to the lips immediately prior to UV exposure isappropriate.

EXAMPLE V

A low SPF suntan cream is prepared by combining the following componentsutilizing conventional mixing techniques.

    ______________________________________                                                               Percent by Weight                                      Component              of Composition                                         ______________________________________                                        Tetrasodium EDTA       0.05                                                   Alkylparabens          0.30                                                   Carbopol (polyacrylic acid polymer-                                                                  0.20                                                   conwnercially available from                                                  B. F. Goodrich Chemical)                                                      Glycerin               2.00                                                   Laureth-23 (polyethylene glycol ether of                                                             3.00                                                   lauryl alcohol)                                                               Sorbitan Stearate      1.50                                                   Octyl Dimethyl PABA    3.00                                                   Dimethicone            2.00                                                   Stearyl Alcohol        6.00                                                   Triethanolamine        0.20                                                   Di-(2-Thienyl) Ethanedione Amphi-Dioxime                                                             2.00                                                   Water (purified)       q.s.                                                   ______________________________________                                    

This cream is useful for topical application to inhibit damage caused byacute or chronic UV exposure. Use of an amount of cream sufficient todeposit about 0.5 mg/cm² of di-(2-thienyl) ethanedione amphi-dioxime,and about 0.5 mg/cm² of the sunscreening agents to the skin immediatelyprior to UV exposure is appropriate.

EXAMPLE VI

A suntan aqueous face gel is prepared by combining the followingcomponents utilizing conventional mixing techniques.

    ______________________________________                                                               Percent by Weight                                      Component              Of Composition                                         ______________________________________                                        Water (purified)       50.00                                                  Aloe                   38.00                                                  Carbopol               1.00                                                   Glycerin               3.00                                                   Methylparaben          0.20                                                   Triethanolamine        0.90                                                   2-Phenyl-Benzimedoic Sulfonic Acid                                                                   2.00                                                   Octoxynol-13 (ethoxylated alkyl phenol                                                               1.50                                                   (C.sub.8 H.sub.17)(C.sub.6 H.sub.4)(OCH.sub.2 CH.sub.2).sub.n OH, n = av.     val. 13)                                                                      Di-(2-Pyrrolyl) Ethanedione Amphi-                                                                   2.00                                                   Dioxime                                                                       Color and Fragrance    q.s.                                                   ______________________________________                                    

This aqueous gel is useful for application to the face to inhibit damagecaused by acute or chronic UV exposure. Use of an amount of gel todeposit about 0.5 mg/cm² of di-(2-pyrrolyl ethanedione amphi-dioxime tothe face immediately prior to UV exposure is appropriate.

EXAMPLE VII

A suntan gel is prepared by combining the following components utilizingconventional mixing techniques.

    ______________________________________                                                               Percent by Weight                                      Component              of Composition                                         ______________________________________                                        Ozokerite Wax          10.00                                                  Paraffin               10.00                                                  Petrolatum             10.00                                                  Isopropyl Myristate    5.00                                                   Mineral Oil            58.00                                                  Octyl Dimethyl PABA    2.50                                                   Propylparaben          0.10                                                   BHA                    0.05                                                   Di-(4-Ethylphenyl) Ethanedione Dioxime                                                               2.00                                                   Naproxen               2.00                                                   Fragrance and Color    q.s.                                                   ______________________________________                                    

This suntan gel is useful for topical application to inhibit damagecaused by acute or chronic UV exposure. Use of an amount of gel todeposit about 0.5 mcJ/cm² of di-(4-ethylphenyl) ethanedione dioxime,about 0.5 mg/cm² of the sunscreening agent, and about 0.1 mg/cm² ofnaproxen to the skin immediately following UV exposure is appropriate.

EXAMPLE VIII

A suntan oil is prepared by combining the following components utilizingconventional mixing techniques.

    ______________________________________                                                               Percent by Weight                                      Component              of Composition                                         ______________________________________                                        Sesame Oil             5.0                                                    Cyclomethicone         20.0                                                   Isopropyl Myristate    5.0                                                    BHA                    0.05                                                   Sorbitan Oleate        1.0                                                    Octyl Dimethyl PABA    1.5                                                    Propylparaben          0.7                                                    Di-(5-Methyl-2-Furyl) Ethanedione Amphi-                                                             2.00                                                   Dioxime                                                                       Mineral Oil            q.s.                                                   ______________________________________                                    

This suntan oil is useful for topical application to inhibit damagecaused by acute or chronic UV exposure. Use of an amount of oilsufficient to deposit about 0.5 mg/cm² of di-(5-methyl-2-furyl)ethanedione amphi-dioxime, and about 0.5 mg/cm² of the sunscreeningagent to the skin immediately prior to UV exposure is appropriate.

EXAMPLE IX

A moisturizing oil-in-water-in-silicone sunscreen emulsion lotion isformed from the following ingredients.

    ______________________________________                                                               Percent by Weight                                      Ingredient             of Composition                                         ______________________________________                                        Aqueous Phase:                                                                Purified Water         58.32                                                  Pantethine, 80% aq. soln. (humectant)                                                                0.10                                                   Methylparaben          0.20                                                   Carbomer viscosity control agent                                                                     0.10                                                   (commercially available in the Acritamer                                      series from R.I.T.A. Corp.)                                                   Glycerin               2.50                                                   Sodim alkyl polyether sulfonate (anionic                                                             0.10                                                   emulsifier)                                                                   Oil Phase:                                                                    Heavy mineral oil      1.75                                                   Cholesterol            1.00                                                   Cetyl palmitate        0.20                                                   PEG-22/Dodecyl glycol copolymer                                                                      0.20                                                   Ethylparaben           0.10                                                   Propylparaben          0.15                                                   Neutralizer Base:                                                             Triethanolamine        0.10                                                   Color & Fragrance:                                                            FD & C Red No. 4 (1% aq. soln.)                                                                      0.03                                                   Odorant Oil            0.30                                                   Silicone Phase:                                                               Cyclomethicone/Dimethicone copolyol                                                                  9.50                                                   (90:10)                                                                       Cyclomethicone/Dimethiconol (13:87)                                                                  5.00                                                   Cyclomethicone         3.00                                                   Phenyl Dimethicone     1.00                                                   Pareth-15-3 (polyethylene glycol ester of a                                                          2.00                                                   mixed synthetic C.sub.11 -C.sub.15 fatty alcohol,                             av. 3 moles EO)                                                               Octyl Methoxycinnamate 7.00                                                   Benzophenone-3         0.50                                                   Naproxen               2.00                                                   Di-1,5-Dimethyl-2-Pyrrolyl Ethanedione                                                               2.00                                                   Amphi-Dioxime                                                                 C.sub.12 -.sub.15 Alcohols Benzoate                                                                  2.85                                                   ______________________________________                                    

In a suitably sized vessel equipped with a suitable mechanical stirrer(Tekmar Model RW-20 stirring motor, manufactured by IKA-WERK, Germany),the water, pantethine, methylparaben, glycerine and sulfonate emulsifierare heated to about 72°-75° C. and mixed. Stirring is increased until avortex forms in the aqueous solution. The thickener, Carbomer, is slowlyadded to the vortex and allowed to mix until completely hydrated and theresultant gel solution is free of gelatinous particles and is uniform incomposition. The temperature is maintained at about 72°-75° C. withconstant agitation.

The oil phase ingredients are added to a separate suitably sized vesseland heated to about 80°-85° C. using slow mechanical stirring once theoil phase becomes molten. At this point the sunscreening agents,naproxen, and di-(1,5-dimethyl-2-pyrrolyl) ethanedione amphi-dioxime aremixed in. When molten, agitation is maintained to keep the oil phaseuniform during heating.

The heated oil phase is then slowly added to the heated water phase withstirring to form the oil-in-water emulsion. After addition is complete,the mechanical stirring means is slowed to avoid unnecessary aeration ofthe emulsion and mixing is continued for approximately fifteen minutesat 70°-75° C. The emulsion is then cooled to about 60° C. with moderateagitation. The base, triethanolamine, is then slowly added to neutralizethe acidic Carbomer 940 and the emulsion (pH 6.5) is mixed at moderatespeed until uniform. The homogeneous oil-in-water emulsion is thencooled to about 45°-50° C. and the colorant and odorant oil are addedfollowed by cooling to room temperature (about 25° C.) with continuedmoderate agitation.

The four silicone fluids and other silicone phase ingredients are mixedtogether in a separate vessel until a uniform silicone phase isattained. The oil-in-water emulsion is slowly added to the siliconephase with stirring until a homogeneous oil-in-water-in-silicone doubleemulsion in lotion form is attained.

This moisturizing lotion is useful for topical application to inhibitdamage caused by acute or chronic UV exposure. Use of an amount oflotion sufficient to deposit about 0.5 mg/cm² ofdi-(1,5-dimethyl-2-pyrrolyl) ethanedione amphi-dioxime, about 0.5 mg/cm²of sunscreening agents, and about 0.1 mg/cm² of naproxen to the skinimmediately following UV exposure is appropriate. This lotion may alsobe applied several times daily, e.g., 2 or 3 times daily, for extendedperiods of time, i.e., greater than one week, in amounts sufficient todeposit about 0.5 mg/cm² of di-(1,5-dimethyl-2-pyrrolyl) ethanedioneamphi-dioxime, about 0.5 mg/cm² of sunscreening agents, and about 0.1mg/cm² of naproxen to the skin to inhibit damage caused by chronic UVexposure.

EXAMPLE X

A skin conditioning toilet bar is prepared from the followingingredients.

    ______________________________________                                                               Percent by Weight                                      Component              of Composition                                         ______________________________________                                        Tallow/Coconut Soap (50/50)                                                                          61.61                                                  Water                  10.00                                                  2-Hydroxypropylglyceryl Ether                                                                        4.00                                                   Sodium Coconut Glyceryl Ether Sulfonate                                                              8.80                                                   Coconut Fatty Acid (CnFA)                                                                            4.00                                                   Di-(3-Ethylphenyl) Ethanedione Amphi-                                                                5.00                                                   Dioxime                                                                       Perfume                1.40                                                   NaCl                   1.04                                                   Na.sub.2 SO.sub.4      0.34                                                   Na.sub.4 EDTA          0.06                                                   TiO.sub.2              0.20                                                   Jaguar C15 (quar hydroxy propyltrimonium                                                             1.00                                                   chloride)                                                                     Merquat 550 (poly quaternium-7)                                                                      1.00                                                   Minors (Colorants, Preservatives, Fillers,                                                           1.55                                                   etc.)                                                                         ______________________________________                                    

The above composition is prepared in the following manner.

Crutching Step

About 127.6 parts of a mix containing: 29.8% water, 52.7% 50/50tallow/coconut (T/Cn) soap, 16.7% sodium coconut glyceryl ethersulfonate paste, 3.3% coconut free fatty acid (CnFA), 3.1%2-hydroxypropylglyceryl ether, and 0.2% NaCl are heated to ca. 150°-200°F. (65°-94° C.). About 10.0 parts of the hydrated polymer JAGUAR C-15are mixed in. The di-(3-ethylphenyl) ethanedione amphi-dioxime is thenadded and mixed in.

Vacuum Drying Step

The crutcher mix is vacuum dried at ca. 50 mm Hg absolute pressure toreduce the moisture content of the mix to ca. 10% and to plod this soapinto noodles. These noodles are passed through a milling step once.

Amalgamating Step

The once-milled soap noodles are weighed and placed in a batchamalgamator. To about 99.1 parts noodles in the amalgamator are added:0.20 part TiO₂, 1.4 parts perfume, 0.15 part colorant solution, 0.15part of a solution which contains ca. 40% EDTA. The combined ingredientsare mixed thoroughly.

Milling Step

Three-roll soap mills are set up with all rolls at 85-105° F (29°-41°C.). The mixture from the amalgamator is passed through the millsseveral times to obtain a homogeneous mix. This is an intimate mixingstep. Plodding and Stamping Steps

A conventional plodder is set up with the barrel temperature at about90° F. (32° C.) and the nose temperature at about 110° F. (43° C.). Theplodder used is a dual stage twin screw plodder that allows for a vacuumof about 40 to 65 mm Hg between the two stages. The soap log extrudedfrom the plodder is typically round or oblong in cross-section, and iscut into individual plugs. These plugs are then stamped on aconventional soap stamping apparatus to yield the finished toilet soapbar.

The use of this toilet bar for cleansing provides a useful means fordeposition of di-(3-ethylphenyl) ethanedione amphidioxime to the skin toinhibit damage caused by acute or chronic UV exposure. Use of the toiletbar such that about 0.05 mg/cm² of di-(3-ethylphenyl) ethanedioneamphi-dioxime is deposited on the skin up to 4 hours prior to UVexposure is appropriate.

EXAMPLE XI

Facial Cleanser

A facial cleanser (lathering mousse composition) is prepared from thefollowing ingredients.

    ______________________________________                                                               Percent by Weight                                      Emulsion Concentrate (A)                                                                             of Composition                                         ______________________________________                                        DRO Water.sup.1        52.63                                                  2-Hydroxypropyglyceryl Ether                                                                         15.00                                                  Sodium Glyceryl Ether Sulfonate                                               (90% Coconut/10 Tallow)-50% Active                                                                   12.06                                                  Sodium Lauroyl Sarcosinate - 33% Active                                                              6.66                                                   PEG 600                4.00                                                   Aloe Vera Gel          1.00                                                   Lexein LP170P (hydrolyzed animal protein)                                                            1.00                                                   Stearic Acid           1.00                                                   Citric Acid            0.30                                                   4,5-Di-(2-Furyl) Furoxan                                                                             5.00                                                   Jaguar C14-S (guar hydroxypropyl-                                                                    0.25                                                   trimonium chloride)                                                           Perfume                0.20                                                   FD & C Red Dye #4      0.20                                                   Lauryl Alcohol         0.20                                                   Alkyl Parabens         0.30                                                   Germall 115 (Imidazolidinyl urea)                                                                    0.10                                                   Na.sub.4 EDTA          0.10                                                   ______________________________________                                         .sup.1 Water purified by double reverse osmosis                          

A-46 Propellant (Isobutane-Propane) (B)

(6.4 g in 100 g concentrate)

The composition is prepared in a single batch process. DRO water isbrought to 71.1° C. and the Jaguar polymer is added with agitation.Maintaining agitation, the following ingredients are added sequentially:Sodium glycerol ether sulfonate, Sodium lauroyl sarcosinate, laurylalcohol, PEG-600, Parabens, EDTA, dye, 2-Hydroxypropylglyceryl ether,stearic acid, Aloe Vera Gel, citric acid and 4,5-di-(2-furyl) furoxan.The mixture is then cooled to 135°-140° F. and the following ingredientsare added sequentially with stirring: Lexein, Germall and perfume. Theresulting mixture is cooled to room temperature.

Aluminum cans are then filled with the cooled emulsion concentrate.Aerosol activator assemblies are then crimped onto the cans to form atight seal. Pressurized A-46 Propellant is then pumped into the cans inan amount sufficient to provide a composition consisting of 6%propellant and 94% emulsion concentrate in each can.

Upon activation of the aerosol assembly, the composition is dispensedunder pressure in the form of a creamy, foaming mousse which can beapplied to the skin for cleansing and as a means for deposition of4,5-di-(2-furyl) furoxan to the skin to inhibit damage caused by acuteor chronic UV exposure. Use of amount of facial cleanser sufficient todeposit about 0.05 mg/cm² of 4,5-di-(2-furyl) furoxan to the skin up to4 hours prior to UV exposure is appropriate.

EXAMPLE XII

A cream soap is prepared by combining the following ingredients asdescribed below.

    ______________________________________                                                               Percent by Weight                                      Component              of Composition                                         ______________________________________                                        Sodium Lauroyl Glutamate                                                                             22.00                                                  (Acylglutamate LS-11) (28)                                                    Sodium Hydrogenated Tallow Glutamate                                                                 3.00                                                   and Cocoyl Glutamate (Acylglutamate                                           GS-11) (28)                                                                   Polyethylene Glycol 400                                                                              10.00                                                  Polyethylene Glycol (M.W. 6300) Mono-                                                                5.00                                                   stearate                                                                      Polyoxyethylene (20) Sorbitan Monostearate                                                           3.00                                                   Di-5-Methyl-2-Pyrrolyl Ethanedione Amphi-                                                            3.00                                                   Dioxime                                                                       Tocopherol Sorbate     5.00                                                   Flufenamic Acid        2.00                                                   2-Ethylhexyl Methoxycinnamate                                                                        3.00                                                   Water                  30.50                                                  Glycerin               10.00                                                  Fragrance and Preservative                                                                           q.s.                                                   ______________________________________                                    

The sodium glutamate, sodium hydrogenated tallow glutamate and cocoylglutamate, polyethylene glycol, polyethylene glycol monostearate,polyoxyethylene sorbitan monostearate, di-5-methyl-2-thienyl ethanedioneamphi-dioxime, tocopherol sorbate, flufenamic acid, 2-ethylhexylmethoxycinnamate, and water are dissolved together with heating. Theglycerin is added with agitation. The mixture is cooled to about 60° C.and the fragrance and preservative are added. The mixture is cooled to35° C. with agitation.

The result is a cream soap the use of which for cleansing provides auseful means for deposition of di-(5-methyl-2-pyrrolyl) ethanedioneamphi-dioxime, tocopherol sorbate, flufenamic acid, and 2-ethylhexylmethoxycinnamate to the skin to inhibit damage caused by acute orchronic UV exposure. Use of an amount of cream soap sufficient todeposit about 0.05 mg/cm² of di-(5-methyl-2-pyrrolyl) ethanedioneamphi-dioxime, 0.05 mg/cm² of tocopherol sorbate, 0.05 mg/cm² of thesunscreening agent, and 0.01 mg/cm² of flufenamic acid to the skin priorto or immediately following UV exposure is appropriate.

EXAMPLE XIII

A shampoo composition is made by combining the following components.

    ______________________________________                                                               Percent by Weight                                      Component              of Composition                                         ______________________________________                                        Ammonium Lauryl Sulfate                                                                              12.0                                                   Ammonium Xylene Sulfonate                                                                            2.2                                                    Ammonium Laureth Sulfate                                                                             4.0                                                    NaCl                   0.5                                                    Di-1-(Methyl-5-Ethyl-2-Pyrrolyl)                                                                     5.0                                                    Ethanedione Amphi-Dioxime                                                     Octyl Dimethyl PABA    7.0                                                    Water                  68.1                                                   Perfume and Minor Ingredients                                                                        1.2                                                    ______________________________________                                    

The ammonium lauryl sulfate, ammonium laureth sulfate, and ammoniumxylene sulfonate are first mixed together. Thedi-(1-methyl-5-ethyl-2-pyrrolyl) ethanedione amphi-dioxime and octyldimethyl PABA and perfume and minor ingredients are added and theresulting mixture is agitated in a Teckmar® Mill set at 70 for 2 minutesat 70° C.

The resulting shampoo composition is added to hair which has been wettedwith water, worked through the hair then rinsed out. This allows fordeposition of di-(1-methyl-5-ethyl-2-pyrrolyl) ethanedione amphi-dioximeand octyl dimethyl PABA to the scalp to inhibit damage caused by acuteor chronic UV exposure. Use of an amount of shampoo sufficient todeposit about 0.05 mg/cm² of di-(1-methyl-5-ethyl-2-pyrrolyl )ethanedione amphi-dioxime and 0.05 mg/cm² of sunscreening agent to thescalp prior to or immediately following UV exposure is appropriate.

What is claimed is:
 1. A topical composition comprising:(a) a safe andeffective amount of one or more α-diamine compounds having thestructure: ##STR17## wherein each --R¹ is independently selected fromthe group consisting of alkyl, aryl, heteroaryl and heterocyclic, or the--R¹ 's are covalently bonded together to form a cyclic alkyl ring; eachheteroaryl, if any, being independently selected from the groupconsisting of furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl,pyrazinyl, pyrimidinyl, pyridazinyl, isoquinolyl, purinyl, phthalazinyl,quinoxalinyl, furazanyl, isoxazolyl, and tetrazolyl; each heterocyclicring, if any, being independently selected from the group consisting ofthe saturated analogs of the above listed group of heteroaryl rings;--R² and --R³ are --OR⁴ in which case there is no bond or polar bondbetween --R² and the nitrogen covalently bonded to --R³, each --R⁴ beingindependently selected from the group consisting of hydrogen, alkyl andaryl, except that both --R⁴ 's are not methyl when both --R¹ 's arefuryl; or --R² -- is --O-- and is covalently bonded to the nitrogenwhich is covalently bonded to --R³, and--R³ is --O-- there being a +charge on the nitrogen to which it is bonded) or nil; wherein theα-diamine compounds consist essentially of compounds wherein ═NR² and═NR³ are in amphi configuration when both --R² and --R³ are --OH, andwhen both --R¹ 's are furyl or the --R¹ 's are covalently bondedtogether to form a cyclohexanedione structure; and (b) apharmaceutically-acceptable topical carrier.
 2. The composition of claim1 wherein the α-diamine compound exhibits at least 20% decrease inOrnithine Decarboxylate Value relative to the Ornithine DecarboxylaseValue of a control in the Standard Method Assay of OrnithineDecarboxylase.
 3. The composition of claim 2 wherein each --R¹ isindependently selected from aryl or heteroaryl selected from the groupconsisting of phenyl, naphthyl, furyl, thienyl, pyrrolyl, imidazolyl,pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, isoquinolyl, purinyl,phthalazinyl, quinoxalinyl, furazanyl, isoxazolyl, and tetrazolyl,wherein any aryl or heteroaryl substituent is selected from hydroxy andC₁ -C₄ alkyl; and wherein both --R⁴ 's are hydrogen.
 4. The compositionof claim 3 wherein the α-diamine compounds consist essentially ofcompounds wherein ═NR² and ═NR³ are in amphi configuration.
 5. Thecomposition of claim 3 wherein --R² -- is --O-- and --R³ is nil, andwherein the two --R¹ 's are the same.
 6. The composition of claim 3wherein --R² -- is --O-- and --R³ is nil, and wherein the two --R¹ 'sare the same.
 7. The composition of either claim 5 or 6 wherein the two--R¹ 's are selected from the group consisting of unsubstituted orsubstituted phenyl, furyl, thienyl, and pyrrolyl.
 8. A topicalcomposition comprising:(a) a safe and effective amount of one or moreα-diamine compounds having the structure: ##STR18## wherein each--R¹ isindependently selected from the group consisting of alkyl, aryl,heteroaryl and heterocyclic or the --R¹ 's are covalently bondedtogether to form a cyclic alkyl ring; each heteroaryl, if any, beingselected from the group consisting of furyl, thienyl, pyrrolyl,imidazolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, isoquinolyl,purinyl, phthalazinyl, quinoxalinyl, furazanyl, isoxazolyl andtetrazolyl; each heterocyclic ring, if any, being independently selectedfrom the group consisting of the saturated analogs of the above listedgroup of heteroaryl rings; wherein the α-diamine compounds consistessentially of compounds wherein the two ═NOH's are in amphiconfiguration when both --R¹ 's are furyl or the --R¹ 's are covalentlybonded to form a cyclohexanedione structure; the α-diamine compoundsexhibiting at least 20% decrease in Ornithine Decarboxylase Valuerelative to the Ornithine Decarboxylase Value of a control in tieStandard Method Assay of Ornithine Decarboxylase; and (b) apharmaceutically-acceptable topical carrier.
 9. The composition of claim8 wherein each --R¹ is aryl or heteroaryl independently selected fromthe group consisting of phenyl, naphthyl, furyl, thienyl, pyrrolyl,imidazolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, isoquinolyl,purinyl, phthalazinyl, quinoxalinyl, furazanyl, isoxazolyl, andtetrazolyl.
 10. The composition of claim 9 wherein each --R¹ isheteroaryl, unsubstituted or mono- or disubstituted with C₁ -C₄ alkyl.11. The composition of claim 10 wherein both R₁ 's are the same.
 12. Thecomposition of claim 9 wherein the --R¹ are selected from the groupconsisting of furyl, thienyl and pyrrolyl, unsubstituted ormonosubstituted with C₁ -C₄ alkyl.
 13. The composition of claim 12wherein both --R¹ 's are the same.
 14. The composition of any of claims10-13 wherein the α-diamine compounds consist essentially of compoundswherein the two ═NOH's are in amphi-configuration.
 15. A method ofprotecting against photodamage of the skin comprising administering tothe skin of a human a topical photoprotective composition of any ofclaims 2, 5, 6, 8, 10, 11, 12 and
 13. 16. A method of protecting againstphoto damage of the skin comprising administering to the skin of a humana composition comprising:(a) a safe and effective amount of one or moreα-diamine compounds having the structure ##STR19## wherein each --R¹ isindependently selected from the group consisting of alkyl, aryl,heteroaryl and heterocyclic, or the R¹ 's are covalently bonded togetherto form a cyclic alkyl ring; each heteroaryl, if any, beingindependently selected from the group consisting of furyl, thienyl,pyrrolyl, imidazolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl,isoquinolyl, purinyl, phthalazinyl, quinoxalinyl, furazanyl, isoxazolyl,and tetrazolyl; each heterocyclic ring, if any, being independentlyselected from the group consisting of the saturated analogs of the abovelisted group of heteroaryl rings; --R² and --R³ are --OR⁴ in which casetiers is no bond or polar bond between --R² and the nitrogen covalentlybonded to --R³, each --R⁴ being independently selected from the groupconsisting of hydrogen, alkyl and aryl, except that both --R⁴ 's are notmethyl when both --R¹ 's are furyl; or --R² -- is --O-- and iscovalently bonded to the nitrogen which is covalently bonded to --R³,and --R³ is --O-- (there being a + charge on the nitrogen to which it isbonded) or nil; wherein the α-diamine compounds consist essentially ofcompounds wherein ═NR² and ═NR³ are in amphi configuration when both--R² and --R³ are --OH, and when both --R¹ 's are furyl or the --R¹ 'sare covalently bonded together to form a cyclohexanedione structure; and(b) a pharmaceutically-acceptable carrier.